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Your search keyword '"Steyaert, Jan"' showing total 9 results
Start Over Author "Steyaert, Jan" Journal nature chemical biology
9 results on '"Steyaert, Jan"'

1. Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist

Author

Masureel, Matthieu, Zou, Yaozhong, Picard, Louis-Philippe, van der Westhuizen, Emma, Mahoney, Jacob P, Rodrigues, João PGLM, Mildorf, Thomas J, Dror, Ron O, Shaw, David E, Bouvier, Michel, Pardon, Els, Steyaert, Jan, Sunahara, Roger K, Weis, William I, Zhang, Cheng, and Kobilka, Brian K

Subjects
Biochemistry and Cell Biology, Medicinal and Biomolecular Chemistry, Chemical Sciences, Biological Sciences, Lung, Respiratory, Adrenergic beta-2 Receptor Agonists, Animals, Antibodies, Asthma, Binding Sites, Computer Simulation, Crystallography, X-Ray, GTP-Binding Proteins, Humans, Hydrogen Bonding, Ligands, Lipids, Mutagenesis, Protein Binding, Protein Conformation, Pulmonary Disease, Chronic Obstructive, Receptors, Adrenergic, beta-2, Salmeterol Xinafoate, Signal Transduction, beta-Arrestins, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Salmeterol is a partial agonist for the β2 adrenergic receptor (β2AR) and the first long-acting β2AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol's safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β2AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β1AR and β2AR explain the high receptor-subtype selectivity. A structural comparison with the β2AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser2045.43 and Asn2936.55. Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol.

Published
2018

6. Publisher Correction: Structural insights into binding specificity, efficacy and bias of a β2AR partial agonist

Author

Masureel, Matthieu, primary, Zou, Yaozhong, additional, Picard, Louis-Philippe, additional, van der Westhuizen, Emma, additional, Mahoney, Jacob P., additional, Rodrigues, João P. G. L. M., additional, Mildorf, Thomas J., additional, Dror, Ron O., additional, Shaw, David E., additional, Bouvier, Michel, additional, Pardon, Els, additional, Steyaert, Jan, additional, Sunahara, Roger K., additional, Weis, William I., additional, Zhang, Cheng, additional, and Kobilka, Brian K., additional

Published
2018
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7. Structural insights into binding specificity, efficacy and bias of a ß2AR partial agonist

Author

Masureel, Matthieu, Zou, Yaozhong, Picard, Louis-Philippe, van der Westhuizen, Emma, Mahoney, Jacob P., Rodrigues, João P. G. L. M., Mildorf, Thomas J., Dror, Ron O., Shaw, David E., Bouvier, Michel, Pardon, Els, Steyaert, Jan, Sunahara, Roger K., Weis, William I., Zhang, Cheng, and Kobilka, Brian K.

Abstract

Salmeterol is a partial agonist for the ß2adrenergic receptor (ß2AR) and the first long-acting ß2AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol’s safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound ß2AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between ß1AR and ß2AR explain the high receptor-subtype selectivity. A structural comparison with the ß2AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser2045.43and Asn2936.55. Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited ß-arrestin recruitment for salmeterol.

Published
2018
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8. A topological switch in CFTR modulates channel activity and sensitivity to unfolding

Author

Cédric Govaerts, Rafael Colomer Martinez, Chloe Martens, Yiting Wang, Maud Sigoillot, Abel Garcia-Pino, Els Pardon, Marie Overtus, Toon Laeremans, Jelle Hendrix, Daniel Scholl, David N. Sheppard, Jan Steyaert, Pardon, Els/0000-0002-2466-0172, Steyaert, Jan/0000-0002-3825-874X, Scholl, Daniel, Sigoillot, Maud, Overtus, Marie, Martinez, Rafael Colomer, Martens, Chloe, Wang, Yiting, Pardon, Els, Laeremans, Toon, Garcia-Pino, Abel, Steyaert, Jan, Sheppard, David N., HENDRIX, Jelle, Govaerts, Cedric, Department of Bio-engineering Sciences, and Structural Biology Brussels

Subjects
Mutation, biology, Chemistry, single-molecule biophysics, ion channels, Cell Biology, Protein degradation, Topology, medicine.disease_cause, Cystic fibrosis transmembrane conductance regulator, chemistry.chemical_compound, Protein structure, Förster resonance energy transfer, protein folding, biology.protein, medicine, Protein folding, Molecular Biology, Adenosine triphosphate, x-ray crystallography, Ion channel
Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the beta-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions. Fonds Forton, Welbio [CR-2012S-04R]; Vaincre la Mucoviscidose, Mukoviszidose e.V; Association Luxembourgeoise de Lutte contre la Mucoviscidose; ABCF2; Chiesi FondationChiesi Pharmaceuticals Inc; Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation; Fibrosis FoundationItalian Cystic Fibrosis Research Foundation; [BB/M012573/1]; CF Foundation Therapeutics; Instruct-ERIC, part of the European Strategy Forum on Research Infrastructures (ESFRI); Instruct-ULTRA 731005; FWO

Published
2021

9. Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist.

Author

Masureel M, Zou Y, Picard LP, van der Westhuizen E, Mahoney JP, Rodrigues JPGLM, Mildorf TJ, Dror RO, Shaw DE, Bouvier M, Pardon E, Steyaert J, Sunahara RK, Weis WI, Zhang C, and Kobilka BK

Subjects
Animals, Antibodies chemistry, Asthma drug therapy, Binding Sites, Computer Simulation, Crystallography, X-Ray, GTP-Binding Proteins chemistry, Humans, Hydrogen Bonding, Ligands, Lipids chemistry, Mutagenesis, Protein Binding, Protein Conformation, Pulmonary Disease, Chronic Obstructive drug therapy, Signal Transduction, beta-Arrestins chemistry, Adrenergic beta-2 Receptor Agonists chemistry, Receptors, Adrenergic, beta-2 chemistry, Salmeterol Xinafoate chemistry
Abstract

Salmeterol is a partial agonist for the β 2 adrenergic receptor (β 2 AR) and the first long-acting β 2 AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol's safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β 2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β 1 AR and β 2 AR explain the high receptor-subtype selectivity. A structural comparison with the β 2 AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204 5.43 and Asn293 6.55 . Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol.

Published
2018
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