Search

Your search keyword '"Equipe de Chimie Organique et Biologie Structurale (ECOBS)"' showing total 13 results
Start Over Author "Equipe de Chimie Organique et Biologie Structurale (ECOBS)" Topic 03 medical and health sciences
13 results on '"Equipe de Chimie Organique et Biologie Structurale (ECOBS)"'

1. Solution structure of the region 51-160 of human KIN17 reveals an atypical winged helix domain

Author

Laure Guilhaudis, Sophie Zinn-Justin, Albane le Maire, Bernard Gilquin, Isabelle Milazzo-Segalas, Joël Couprie, Marie Courçon, Ludovic Carlier, Muriel Gondry, Daniel Davoust, Mireille Moutiez, Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut de Biologie et de Technologies de Saclay (IBITECS), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Equipe de Chimie Organique et Biologie Structurale ( ECOBS ), Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut de Biologie et de Technologies de Saclay ( IBITECS ), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
Models, Molecular, Stereochemistry, Protein Conformation, Recombinant Fusion Proteins, Genetic Vectors, Molecular Sequence Data, Sequence alignment, RNA-binding protein, Winged Helix, Biology, Biochemistry, Protein Structure, Secondary, 03 medical and health sciences, Protein structure, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Animals, Humans, Amino Acid Sequence, Winged-Helix Transcription Factors, Molecular Biology, Peptide sequence, Nuclear Magnetic Resonance, Biomolecular, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, Zinc finger, 0303 health sciences, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 030302 biochemistry & molecular biology, RNA-Binding Proteins, Zinc Fingers, Protein Structure, Tertiary, DNA-Binding Proteins, Protein Structure Report, Helix, Winged-helix transcription factors, Sequence Alignment
Abstract

Human KIN17 is a 45-kDa eukaryotic DNA- and RNA-binding protein that plays an important role in nuclear metabolism and in particular in the general response to genotoxics. Its amino acids sequence contains a zinc finger motif (residues 28-50) within a 30-kDa N-terminal region conserved from yeast to human, and a 15-kDa C-terminal tandem of SH3-like subdomains (residues 268-393) only found in higher eukaryotes. Here we report the solution structure of the region 51-160 of human KIN17. We show that this fragment folds into a three-alpha-helix bundle packed against a three-stranded beta-sheet. It belongs to the winged helix (WH) family. Structural comparison with analogous WH domains reveals that KIN17 WH module presents an additional and highly conserved 3(10)-helix. Moreover, KIN17 WH helix H3 is not positively charged as in classical DNA-binding WH domains. Thus, human KIN17 region 51-160 might rather be involved in protein-protein interaction through its conserved surface centered on the 3(10)-helix.

Published
2009

2. Structure–activity relationships of urotensin II and URP

Author

Hubert Vaudry, David Chatenet, Daniel Davoust, Pierre Pacaud, Christophe Dubessy, Laure Guilhaudis, Alain Fournier, Bruno Pfeiffer, Hassan Oulyadi, Marie-Christine Tonon, Jérôme Leprince, Pierre Renard, Elizabeth Scalbert, Isabelle Ségalas-Milazzo, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Montreal Heart Institute (MONTREAL HEART INSTITUTE), Les Laboratoires SERVIER, Institut de Recherche Servier, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)

Subjects
Protein Conformation, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peptide Hormones, Peptide, Endogeny, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, MESH: Tyrosine, chemistry.chemical_compound, MESH: Protein Conformation, MESH: Structure-Activity Relationship, 0302 clinical medicine, Endocrinology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, Disulfides, MESH: Peptide Fragments, Receptor, chemistry.chemical_classification, 0303 health sciences, Alanine, Molecular Structure, Biological activity, 3. Good health, Amino acid, MESH: Alanine, Urotensins, MESH: Molecular Structure, Molecular Sequence Data, MESH: Sequence Alignment, Structure-Activity Relationship, 03 medical and health sciences, Cellular and Molecular Neuroscience, Animals, Humans, Structure–activity relationship, MESH: Disulfides, Amino Acid Sequence, Cysteine, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, MESH: Urotensins, Rational design, MESH: Cysteine, Peptide Fragments, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, Tyrosine, Urotensin-II, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

International audience; Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure-activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4-11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free alpha-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand-receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.

Published
2008
Full Text
View/download PDF

3. Structure of the MutL$\alpha$ C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site

Author

Bernard Gilquin, Floriana Londino, Josan A Márquez, Pierre Bonnesoeur, Claudine Dherin, Serge Boiteux, Marie-Hélène Le Du, Carine Tellier-Lebegue, Muriel Gondry, Jean-Baptiste Charbonnier, Pierre Legrand, Mireille Moutiez, Cathy Quemener, Emeric Gueneau, Laboratoire de Biologie Structurale et Radiobiologie (LBSR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Radiobiologie moléculaire et cellulaire (RMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Systèmes membranaires, photobiologie, stress et détoxification (SMPSD - UMR 8221), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie et de Technologies de Saclay (IBITECS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), European Project: 227764,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2008-1,PCUBE(2009), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Models, Molecular, congenital, hereditary, and neonatal diseases and abnormalities, HMG-box, Saccharomyces cerevisiae, MLH1, Protein Structure, Secondary, 03 medical and health sciences, Endonuclease, 0302 clinical medicine, Protein structure, MutL Proteins, Structural Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, neoplasms, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Genetics, 0303 health sciences, biology, Chemistry, Nuclear Proteins, nutritional and metabolic diseases, Endonucleases, biology.organism_classification, digestive system diseases, DNA Repair Enzymes, 030220 oncology & carcinogenesis, biology.protein, MutL Protein Homolog 1, Homologous recombination
Abstract

International audience; Mismatch-repair factors have a prominent role in surveying eukaryotic DNA-replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutLα (Mlh1-Pms1 heterodimer) C-terminal domain (CTD) from $Saccharomyces\ cerevisiae$, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutLα as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutLα(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs.

Published
2013
Full Text
View/download PDF

4. The C-terminal domain of the Uup protein is a DNA-binding coiled coil motif

Author

Olivier Lequin, Elie Dassa, A. Sander Haase, Ludovic Carlier, Monica Y. Burgos Zepeda, Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Université Pierre et Marie Curie - Paris 6 (UPMC), Membranes bactériennes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
DNA, Bacterial, Models, Molecular, Subfamily, Magnetic Resonance Spectroscopy, Stereochemistry, 030303 biophysics, Molecular Sequence Data, Biology, Antiparallel (biochemistry), DNA-binding protein, Protein Structure, Secondary, 03 medical and health sciences, chemistry.chemical_compound, Structural Biology, Escherichia coli, A-DNA, Amino Acid Sequence, 030304 developmental biology, Coiled coil, 0303 health sciences, Binding Sites, [CHIM.ORGA]Chemical Sciences/Organic chemistry, C-terminus, Escherichia coli Proteins, Protein Structure, Tertiary, DNA-Binding Proteins, Biochemistry, chemistry, Structural Homology, Protein, ATP-Binding Cassette Transporters, CTD, Hydrophobic and Hydrophilic Interactions, Sequence Alignment, DNA, Protein Binding
Abstract

International audience; The bacterial Uup protein belongs to the REG subfamily of soluble ATP-binding cassette (ABC) ATPases, and is implicated in precise excision of transposons. In Escherichia coli, the uup gene encodes a 72kDa polypeptide that comprises two ABC domains, separated by a linker region, and a 12kDa C-terminal domain (CTD). Uup binds double-stranded DNA with no sequence specificity, and we previously demonstrated that the CTD domain is a crucial region that participates in DNA-binding activity. We report herein the NMR structure of Uup CTD, consisting of an intramolecular antiparallel two-stranded coiled coil motif. Structural comparison with analogous coiled coil domains reveals that Uup CTD contains an atypical 3(10)-helix in the α-hairpin region that contributes to the hydrophobic core. Using NMR titration experiments, we identified residues of the CTD domain involved in the binding to double-stranded DNA. These residues are located on two opposite surfaces at the base of the coiled coil, formed by the N- and C-terminal extremities, where a strictly conserved proline residue induces an overwinding of the coiled coil. Finally, preliminary analysis of NMR spectra recorded on distinct Uup constructs precludes a fully flexible positioning of the CTD domain in full-length Uup. These structural data are the first reported for a non-ATPase domain within ABC REG subfamily.

Published
2012
Full Text
View/download PDF

5. Secondary structure and NMR resonance assignments of the C-terminal DNA-binding domain of Uup protein

Author

Ludovic Carlier, Elie Dassa, Monica Y. Burgos Zepeda, A. Sander Haase, Olivier Lequin, Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Université Pierre et Marie Curie - Paris 6 (UPMC), Membranes bactériennes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Synthèse, Structure et Fonction de Molécules Bioactives (SSFMB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
DNA repair, Biology, Biochemistry, Protein Structure, Secondary, 03 medical and health sciences, chemistry.chemical_compound, Structural Biology, ATP hydrolysis, Tn10, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, Protein secondary structure, 030304 developmental biology, Coiled coil, 0303 health sciences, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Escherichia coli Proteins, 030302 biochemistry & molecular biology, DNA-binding domain, Nuclear magnetic resonance spectroscopy, Protein Structure, Tertiary, DNA-Binding Proteins, chemistry, ATP-Binding Cassette Transporters, DNA
Abstract

International audience; ATP-binding cassette (ABC) systems belong to a large superfamily of proteins that couple the energy released from ATP hydrolysis to a wide variety of cellular processes, including not only transport of various molecules, but also gene regulation, and DNA repair. Mutations in the bacterial uup gene, which encodes a cytosolic ABC ATPase, lead to an increase in the frequency of precise excision of transposons Tn10 and Tn5, suggesting a role of the Uup protein in DNA metabolism. Uup is a 72 kDa polypeptide which comprises two ABC domains, separated by a 75-residue linker, and a C-terminal domain (CTD) of unknown function. The Uup protein from Escherichia coli has been shown to bind DNA in vitro, and the CTD domain contributes to the DNA-binding affinity. We have produced and purified uniformly labeled (15)N- and (15)N/(13)C Uup CTD domain (region 528-635), and assigned backbone and side-chains resonances using heteronuclear NMR spectroscopy. Secondary structure evaluation based on backbone chemical shifts is consistent with the presence of three α-helices, including two long ones (residues 564-590 and 601-632), suggesting that Uup CTD may fold as an intramolecular coiled coil motif. This work provides the starting point towards determining the first atomic structure of a non-ATPase domain within the vast REG subfamily of ABC soluble ATPases.

Published
2012
Full Text
View/download PDF

6. NMR resonance assignments of NarE, a putative ADP-ribosylating toxin from Neisseria meningitidis

Author

Carlier, L.P.A., Köhler, Christian, Veggi, D., Pizza, M., Soriani, M., Boelens, R., Bonvin, A.M.J.J., NMR Spectroscopy, Sub NMR Spectroscopy, Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Université Pierre et Marie Curie - Paris 6 (UPMC), NMR Spectroscopy, and Sub NMR Spectroscopy

Subjects
030303 biophysics, Bacterial Toxins, Molecular Sequence Data, ADP Ribose Transferases, Biology, Neisseria meningitidis, medicine.disease_cause, Biochemistry, Protein Structure, Secondary, Article, 03 medical and health sciences, chemistry.chemical_compound, Structural Biology, medicine, NarE, Meningitis, Amino Acid Sequence, Peptide sequence, Nuclear Magnetic Resonance, Biomolecular, 030304 developmental biology, 0303 health sciences, Adenosine Diphosphate Ribose, Adenosine diphosphate ribose, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Nuclear magnetic resonance spectroscopy, NMR, Heteronuclear molecule, chemistry, ADP ribosylation, ADP-ribosylation, Pathogenic bacteria, Target protein
Abstract

International audience; NarE is a 16 kDa protein identified from Neisseria meningitidis, one of the bacterial pathogens responsible for meningitis. NarE belongs to the ADP-ribosyltransferase family and catalyses the transfer of ADP-ribose moieties to arginine residues in target protein acceptors. Many pathogenic bacteria utilize ADP-ribosylating toxins to modify and alter essential functions of eukaryotic cells. NarE was proposed to bind iron through a Fe-S center which is supposed to be implied in catalysis. We have produced and purified uniformly labeled (15)N- and (15)N/(13)C-NarE and assigned backbone and side-chain resonances using multidimensional heteronuclear NMR spectroscopy. These assignments provide the starting point for the three-dimensional structure determination of NarE and the characterization of the role of the Fe-S center in the catalytic mechanism.

Published
2011
Full Text
View/download PDF

7. Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells

Author

Schouft, Marie-Thérèse, Fontaine, Marc, Scalbert, Elisabeth, Malagon, Maria, Gandolfo, Pierrick, Desrues, Laurence, Cellier, Eric, Decker, Annick, Clerens, Stefan, Vandesande, Frans, Do-Rego, C., Beauvillain, C., Baroncini, Marc, Balment, Richard, Dujardin, Cynthia, Tollemer, Helene, BRUZZONE, FEDERICA, Tollemer, Hélène, Do-Régo, Jean, Simonnet, Guy, VALLARINO, MAURO, Beauvillain, Jean, Costentin, Jean, Do-Régo, Jean-Claude, Beauvillain, Jean-Claude, Chartrel, C, Alvear-Perez, P, Iturrioz, X., Reaux-Le Goazigo, A., Audinot, V., Chomarat, C, Coge, C, Nosjean, O., Rodriguez, M., Galizzi, J., Goazigo, R., Chomarat, P., Coge, F., Chartrel, Nicolas, Alonzeau, Jessy, Alexandre, David, Jeandel, Jean, Alvear-Perez, Rodrigo, Boutin, Jean, Anouar, Youssef, Llorens-Cortes, Catherine, Jeandel, Lydie, Carlier, Ludovic, Ségalas-Milazzo, Isabelle, Guilhaudis, Laure, Oulyadi, Hassan, Davoust, Daniel, Dubessy, Christophe, Scalbert, Elizabeth, Pfeiffer, Bruno, Renard, Pierre, Lihrmann, Isabelle, Pacaud, Pierre, Chevrier, Lucie, De Brevern, Alexandre, Hernandez, Eva, Guedj, Anne Marie, de Roux, Nicolas, Cholez, V, Debuysscher, V, Bourgeais, B, Boudot, B, Tron, F., Brassart, B., Regnier, A., Bissac, E, Pecnard, E, Gouilleux, F., Lassoued, K, Gouilleux-Gruart, V, Cholez, E, Bourgeais, J, Boudot, C., Gouilleux, V, Chuquet, Julien, Lecrux, Clotilde, Chatenet, David, Chazalviel, Laurent, Roussel, Simon, MacKenzie, Eric, Touzani, Omar, Tonon, M.C, Li, S., Leprince, J�r�me, Tonon, M.C., Compère, M, Lanfray, D, Castel, Hélène, Morin, M., Leprince, Jérôme, Dureuil, B, Vaudry, Hubert, Pelletier, G., Tonon, Marie-Christine, Compère, V., Morin, F., Dureuil, D, Vaudry, V, inconnu, Inconnu, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Chercheur indépendant, Laboratoire de l'intégration, du matériau au système (IMS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, University of Córdoba [Córdoba], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, UMR 5287, Homéostasie-Allostasie-Pathologie-Réhabilitation, Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Servier, Centre de Recherches de Croissy, ESPE de l'Académie d'Amiens, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Université Henri Poincaré - Nancy 1 (UHP), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatique génomique et moléculaire ((U 726)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service des Maladies Métaboliques et Endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Henri Becquerel-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), STMicroelectronics, Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Neurodégénérescence : modèles et stratégies thérapeutiques (NMST), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), IRCELYON-Ingéniérie, du matériau au réacteur (ING), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Télécom SudParis (TSP), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Rouen, Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université Le Havre Normandie (ULH), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Leptin, Male, Transcription, Genetic, MESH: Sequence Homology, Amino Acid, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Energy homeostasis, MESH: Down-Regulation, MESH: Ependyma, Mice, 0302 clinical medicine, Endocrinology, Lateral Ventricles, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Insulin, MESH: Animals, MESH: Proline-Rich Protein Domains, MESH: Peptide Fragments, MESH: Lateral Ventricles, Diazepam Binding Inhibitor, 2. Zero hunger, 0303 health sciences, MESH: Ranidae, MESH: Receptors, Kisspeptin-1, Fasting, medicine.anatomical_structure, Hypothalamus, Neuroglia, MESH: Neuroglia, Ependyma, Diazepam binding inhibitor, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, Protein Binding, MESH: Protein Transport, medicine.medical_specialty, MESH: Rats, Central nervous system, Down-Regulation, Neuropeptide, MESH: Fasting, MESH: Insulin, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Protein Binding, Molecular Biology, MESH: Mice, Third Ventricle, MESH: RNA, Messenger, 030304 developmental biology, MESH: Transcription, Genetic, Neuropeptides, MESH: Time Factors, MESH: Rats, Wistar, MESH: Leptin, MESH: Hypothalamus, Peptide Fragments, MESH: Male, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, 030217 neurology & neurosurgery, MESH: Third Ventricle
Abstract

In the central nervous system of mammals, the gene encoding diazepam-binding inhibitor (DBI) is exclusively expressed in glial cells. Previous studies have shown that central administration of a DBI processing product, the octadecaneuropeptide ODN, causes a marked inhibition of food consumption in rodents. Paradoxically, however, the effect of food restriction on DBI gene expression has never been investigated. Here, we show that in mice, acute fasting dramatically reduces DBI mRNA levels in the hypothalamus and the ependyma bordering the third and lateral ventricles. I.p. injection of insulin, but not of leptin, selectively stimulated DBI expression in the lateral ventricle area. These data support the notion that glial cells, through the production of endozepines, may relay peripheral signals to neurons involved in the central regulation of energy homeostasis.

Published
2010
Full Text
View/download PDF

8. Structural and pharmacological characteristics of chimeric peptides derived from peptide E and beta-endorphin reveal the crucial role of the C-terminal YGGFL and YKKGE motifs in their analgesic properties

Author

Jérôme Leprince, Hubert Vaudry, Karine Courchay, Catherine Mayer, Jean-Claude do Rego, Jean Costentin, Daniel Davoust, Eric Condamine, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)

Subjects
Male, Circular dichroism, Magnetic Resonance Spectroscopy, Physiology, Amino Acid Motifs, Molecular Sequence Data, Pain, Peptide, 010402 general chemistry, 01 natural sciences, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, Structure-Activity Relationship, Endocrinology, Proopiomelanocortin, Animals, Amino Acid Sequence, Opioid peptide, Receptor, Peptide sequence, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Analgesics, biology, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Circular Dichroism, beta-Endorphin, Enkephalins, Random coil, 0104 chemical sciences, biology.protein, Peptides, Alpha helix
Abstract

International audience; Peptide E (a 25-amino acid peptide derived from proenkephalin A) and beta-endorphin (a 31-amino acid peptide derived from proopiomelanocortin) bind with high affinity to opioid receptors and share structural similarities but induce analgesic effects of very different intensity. Indeed, whereas they possess the same N-terminus Met-enkephalin message sequence linked to a helix by a flexible spacer and a C-terminal part in random coil conformation, in contrast with peptide E, beta-endorphin produces a profound analgesia. To determine the key structural elements explaining this very divergent opioid activity, we have compared the structural and pharmacological characteristics of several chimeric peptides derived from peptide E and beta-endorphin. Structures were obtained under the same experimental conditions using circular dichroism, computational estimation of helical content and/or nuclear magnetic resonance spectroscopy (NMR) and NMR-restrained molecular modeling. The hot-plate and writhing tests were used in mice to evaluate the antinociceptive effects of the peptides. Our results indicate that neither the length nor the physicochemical profile of the spacer plays a fundamental role in analgesia. On the other hand, while the functional importance of the helix cannot be excluded, the last 5 residues in the C-terminal part seem to be crucial for the expression or absence of the analgesic activity of these peptides. These data raise the question of the true function of peptides E in opioidergic systems.

Published
2009
Full Text
View/download PDF

9. In Vivo and in Vitro Structure-Activity Relationships and Structural Conformation of Kisspeptin-10-Related Peptides

Author

Gutiérrez-Pascual, Ester, Leprince, Jérôme, Martínez-Fuentes, Antonio, Ségalas-Milazzo, Isabelle, Pineda, Rafael, Roa, Juan, Duran-Prado, Mario, Guilhaudis, Laure, Desperrois, Elia, Lebreton, Aurélie, Pinilla, Leonor, Tonon, Marie-Christine, Vaudry, Hubert, Tena-Sempere, Manuel, Castaño, Justo, Gutierrez-Pascual, E., Martinez-Fuentes, J., Segalas-Milazzo, I., Malagon, Maria, Castano, J., Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Département hématologie, Centre Hospitalier Universitaire (CHU), Department of Cell Biology, and University of Córdoba [Córdoba]

Subjects
Male, Magnetic Resonance Spectroscopy, Protein Conformation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Cricetinae, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 0302 clinical medicine, Kisspeptin, Protein structure, MESH: Protein Conformation, MESH: Structure-Activity Relationship, MESH: Cricetulus, Cricetinae, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, Receptor, 0303 health sciences, Kisspeptins, MESH: Kisspeptins, Chinese hamster ovary cell, Biochemistry, MESH: Oligopeptides, Molecular Medicine, Oligopeptides, MESH: Rats, Molecular Sequence Data, CHO Cells, Biology, 03 medical and health sciences, Structure-Activity Relationship, Cricetulus, In vivo, MESH: CHO Cells, MESH: Luteinizing Hormone, Structure–activity relationship, Animals, Amino Acid Sequence, Rats, Wistar, 030304 developmental biology, Pharmacology, MESH: Molecular Sequence Data, MESH: Magnetic Resonance Spectroscopy, MESH: Rats, Wistar, Luteinizing Hormone, In vitro, MESH: Male, Rats, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030217 neurology & neurosurgery
Abstract

International audience; Kisspeptins, the natural ligands of the G protein-coupled receptor KISS1R, comprise a family of related peptides derived from the proteolytic processing of a common precursor encoded by the KISS1 gene. Among those, Kisspeptin-10 (Kp-10) contains the basic residues to retain full functional activity and exhibits higher receptor affinity and biopotency than longer forms of the peptide. Although kisspeptins were first characterized by their ability to inhibit tumor metastasis, recent studies have revealed that the KISS1/KISS1R system plays an essential role in the neuroendocrine control of the reproductive axis. In this context, development and functional analysis of Kp-10 analogs may help in the search for new agonists and antagonists as valuable tools to manipulate the KISS1/KISS1R system and hence fertility. We report herein functional and structural analyses of a series of Ala-substituted rat kp-10 analogs, involving [Ca(2+)](i) responses in rat kiss1r-transfected Chinese hamster ovary cells, dynamic luteinizing hormone (LH) responses in vivo, and NMR structural studies. In vitro assays revealed that Ala substitutions in positions 6 or 10 of kp-10 resulted in a significant increase in EC(50) values (>6.46 x 10(-6) M versus 1.54 to 2.6 x 10(-8) M for rat and human Kp-10, respectively) and a substantial decrease in the proportion of responsive cells coupled to a marked increase in the time required to reach maximal response. In vivo assays showed that Ala(6) substitution diminished and Ala(10) substitution eliminated LH secretory responses, whereas coadministration of each analog failed to affect the LH-releasing ability of kp-10. Molecular modeling under NMR restraints revealed that kp-10 exhibits a helicoidal structure between the Asn(4) and Tyr(10) residues, with mixed alpha- and 3(10)-helix characteristics. Ala(6) substitution induced limited destabilization of the helix around the position of the substitution. Ala(10) substitution was found to totally disrupt the helical structure in the C-terminal region of the molecule. Taken together, our results indicate that positions 6 and 10 are critical for kp-10 action at kiss1r and suggest that modifications in these positions could lead to the generation of new kisspeptin agonists and/or antagonists with altered functional and perhaps binding properties. Furthermore, they emphasize the importance of using combined, multidisciplinary approaches, including in vivo studies, to reliably evaluate structure function properties of novel kisspeptin analogs.

Published
2009
Full Text
View/download PDF

10. Molecular and conformational determinants of pituitary adenylate cyclase-activating polypeptide (PACAP) for activation of the PAC1 receptor

Author

David Vaudry, Steve Bourgault, Marc Laburthe, Isabelle Ségalas-Milazzo, Alain Couvineau, Laure Guilhaudis, Alain Fournier, Hubert Vaudry, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), International Associated laboratory Samuel de Champlain, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Scientifique [Québec] (INRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by the Institut National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale (INSERM U413), the Conseil Régional de Haute-Normandie, the IREB, the IRME, the ANR, and a scientific exchange program from INSERM and the Fonds de la Recherche en Sante' du Que'bec (FRSQ). Parts of these studies were performed with the support of the Platform for Cell Imaging of Haute-Normandie (PRIMACEN). NMR and molecular modeling software facilities were provided by the Centre de Ressources Informatiques de Haute-Normandie

Subjects
Agonist, Magnetic Resonance Spectroscopy, MESH: Amino Acids, Protein Conformation, medicine.drug_class, Adenylate kinase, MESH: Cricetinae, CHO Cells, Cyclase, Turn (biochemistry), Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, 0302 clinical medicine, MESH: Structure-Activity Relationship, MESH: Protein Conformation, MESH: Cricetulus, MESH: CHO Cells, Cricetinae, Drug Discovery, Peptide synthesis, medicine, Animals, MESH: Protein Binding, MESH: Animals, Amino Acids, 030304 developmental biology, G protein-coupled receptor, 0303 health sciences, MESH: Magnetic Resonance Spectroscopy, MESH: Pituitary Adenylate Cyclase-Activating Polypeptide, Pituitary adenylate cyclase-activating peptide, chemistry, Biochemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, MESH: Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Pituitary Adenylate Cyclase-Activating Polypeptide, Molecular Medicine, Pharmacophore, 030217 neurology & neurosurgery, Protein Binding, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Abstract

International audience; PAC1 receptor is abundant in the CNS and plays an important role in neuronal survival. To identify the molecular determinants and the conformational components responsible for the activation of the PAC1 receptor, we performed a SAR study focusing on the N-terminal domain of its endogenous ligand, PACAP. This approach revealed that residues Asp(3) and Phe(6) are key elements of the pharmacophore of the PAC1 receptor. This study, supported by NMR structural analyses, suggests that the N-terminal tail of PACAP (residues 1 to 4) adopts a specific conformation similar to a turn when it activates the PAC1 receptor. Moreover, the integrity of the alpha-helix conformation observed at positions 5 to 7 appears crucial to allow the binding of PACAP. Characterization of analogues led to the identification of several superagonists, such as [Bip(6)]PACAP27, and of a new potent PAC1 receptor antagonist, [Sar(4)]PACAP38. The bioactive conformation inferred from this SAR study could constitute an appropriate molecular scaffold supporting the design of nonpeptidic PAC1 receptor agonists.

Published
2009
Full Text
View/download PDF

11. Characterization of urotensin-II receptor structural domains involved in the recognition of U-II, URP, and urantide

Author

Stéphane Boivin, Isabelle Milazzo, Laure Guilhaudis, Alain Fournier, Daniel Davoust, Hassan Oulyadi, Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), and Financial support was obtained from the Canadian Institutes for Health Research (CIHR), the Ministère de l'Education du Québec, and the Région de la Haute Normandie

Subjects
Circular dichroism, Stereochemistry, Peptide Hormones, Urotensins, Molecular Sequence Data, MESH: Protein Structure, Secondary, Peptide, MESH: Amino Acid Sequence, MESH: Receptors, G-Protein-Coupled, Urotensin-II receptor, Biochemistry, Micelle, Protein Structure, Secondary, MESH: Circular Dichroism, Receptors, G-Protein-Coupled, 03 medical and health sciences, Extracellular, Amino Acid Sequence, Surface plasmon resonance, MESH: Peptide Fragments, Receptor, Micelles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Molecular Sequence Data, MESH: Urotensins, Circular Dichroism, 030302 biochemistry & molecular biology, MESH: Micelles, Intracellular Signaling Peptides and Proteins, Surface Plasmon Resonance, Peptide Fragments, MESH: Surface Plasmon Resonance, Transmembrane domain, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, MESH: Peptide Hormones
Abstract

International audience; Urotensin-II (U-II) and urotensin-II-related peptide (URP) are potent vasoconstrictors, and this action is mediated through a G protein-coupled receptor identified as UT. This receptor is expressed abundantly in the mammalian cardiovasculature, and the effects of U-II and URP can be blocked with urantide, a selective antagonist. Thus, we carried out a study with the aim to characterize the conformational arrangement of the three extracellular loops of UT as well as the transmembrane domains III and IV. Secondary structures of the synthetic receptor fragments were determined using circular dichroism (CD) spectroscopy in a variety of solvent and micelle conditions. Spectra showed that all receptor segments but not the extracellular loop I exhibited a propensity for adopting the alpha-helix folding. Furthermore, using surface plasmon resonance (SPR) technology, we measured the binding affinities of the ligands, U-II, URP, and urantide toward the UT extracellular segments. SPR data showed that both U-II and URP bind extracellular loops II and III with similar affinities, whereas none of these two ligands were able to interact with the extracellular loop I. Moreover, the binding of urantide was observed only with the second extracellular loop. These results imply that U-II and URP but not urantide would bind to UT according to a common pattern. Also, the correlation of the CD spectral information with the affinity data suggested that the adoption of a helical geometry in UT, by extracellular loops II and III, might be essential for favoring the binding of ligands.

Published
2006
Full Text
View/download PDF

12. Structure and functions of the novel hypothalamic RFamide neuropeptides R-RFa and 26RFa in vertebrates

Author

Chartrel, Nicolas, BRUZZONE, FEDERICA, Leprince, Jérôme, Tollemer, Hélène, Anouar, Youssef, Do-Régo, Jean, Ségalas-Milazzo, Isabelle, Guilhaudis, Laure, Cosette, Pascal, Jouenne, Thierry, Simonnet, Guy, VALLARINO, MAURO, Beauvillain, Jean, Costentin, Jean, Vaudry, Hubert, Do-Régo, Jean-Claude, Beauvillain, Jean-Claude, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Polymères Biopolymères Surfaces (PBS), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Polymères, biopolymères, membranes (PBM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), UMR 5287, Homéostasie-Allostasie-Pathologie-Réhabilitation, Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille

Subjects
Central Nervous System, Receptors, Neuropeptide, Amphibian, Ranidae, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Central nervous system, Hypothalamus, Neuropeptide, Peptide, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Endocrinology, biology.animal, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Animals, Humans, MESH: Central Nervous System, MESH: Animals, Receptor, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Humans, biology, MESH: Ranidae, MESH: Receptors, Neuropeptide, Neuropeptides, Protein primary structure, Vertebrate, MESH: Hypothalamus, Cell biology, medicine.anatomical_structure, chemistry, MESH: Oligopeptides, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Oligopeptides, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; A number of RFamide peptides have been characterized in invertebrate species and these peptides have been found to exert a broad spectrum of biological activities. In contrast, in vertebrates, our knowledge on RFamide peptides is far more limited and only a few members of the RFamide peptide family have been identified in various vertebrate classes during the last years. The present review focuses on two novel RFamide peptides, Rana RFamide (R-RFa) and 26RFa, that have been recently isolated from the amphibian brain. R-RFa shares the C-terminal LPLRFamide motif with other RFamide peptides previously identified in mammals, birds and fish. The distribution of R-RFa in the frog brain exhibits strong similarities with those of other LPLRFamide peptides, notably in the periventricular region of the hypothalamus. There is also evidence that the physiological functions of R-RFa and other LPLRFamide peptides have been conserved from fish to mammals; in particular, all these peptides appear to be involved in the control of pituitary hormone secretion. 26RFa does not exhibit any significant structural identity with other RFamide peptides and this peptide is the only member of the family that possesses an FRFamide motif at its C-terminus. The strong conservation of the primary structure of 26RFa from amphibians to mammals suggests that this RFamide peptide is involved in important biological functions in vertebrates. As for several other RFamide peptides, 26RFa-containing neurons are present in the hypothalamus, notably in two nuclei involved in the control of feeding behavior. Indeed, 26RFa is a potent stimulator of appetite in mammals. Concurrently, recent data suggest that 26RFa exerts various neuroendocrine regulatory activities at the pituitary and adrenal level.

Published
2006
Full Text
View/download PDF

13. Structure–activity relationships and structural conformation of a novel urotensin II-related peptide

Author

Hassan Oulyadi, Cédric Boularan, Pierre Renard, Pierre Pacaud, Isabelle Ségalas-Milazzo, Laure Guilhaudis, Isabelle Lihrmann, David Chatenet, Jérôme Leprince, Christophe Dubessy, Bruno Pfeiffer, Hubert Vaudry, Daniel Davoust, Ludovic Carlier, Elizabeth Scalbert, Marie-Christine Tonon, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Université de Nantes (UN), Université de Picardie Jules Verne (UPJV), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Models, Molecular, Protein Conformation, Physiology, Stereochemistry, Peptide Hormones, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Molecular Sequence Data, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Urotensin-II receptor, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH: Protein Conformation, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, MESH: Animals, Amino Acid Sequence, Receptor, MESH: Peptide Fragments, MESH: Organ Specificity, 030304 developmental biology, chemistry.chemical_classification, Alanine, 0303 health sciences, MESH: Humans, MESH: Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Rational design, Antagonist, Biological activity, Peptide Fragments, 3. Good health, chemistry, Organ Specificity, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, Urotensin-II, 030217 neurology & neurosurgery, MESH: Models, Molecular
Abstract

Urotensin II (UII) has been described as the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. Recently, a UII-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala- Cys-Phe-Trp-Lys-Tyr-Cys- Val-OH. In order to study the structure–function relationships of URP, we have synthesized a series of URP analogs and measured their binding affinity on h GPR14-transfected cells and their contractile activity in a rat aortic ring bioassay. Alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala 8 -substituted analog that retained biological activity. Most importantly, d -scan of URP revealed that [ d -Trp 4 ]URP abrogated and [ d -Tyr 6 ]URP partially suppressed the UII-evoked contractile response. [Orn 5 ]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1 H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse γ-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP. These pharmacological and structural data should prove useful for the rational design of non-peptide ligands as potential GPR14 agonists and antagonists.

Published
2004
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results