15 results on '"Kroemer RT"'
Search Results
2. Comparison of the 3D models of four different human IL-7 isoforms with human and murine IL-7.
- Author
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Kroemer, RT, Kröncke, R, Gerdes, J, and Richards, WG
- Published
- 1998
- Full Text
- View/download PDF
Catalog
3. Entropy from state probabilities: hydration entropy of cations.
- Author
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Huber RG, Fuchs JE, von Grafenstein S, Laner M, Wallnoefer HG, Abdelkader N, Kroemer RT, and Liedl KR
- Subjects
- Cations chemistry, Entropy, Metals chemistry, Molecular Dynamics Simulation, Water chemistry
- Abstract
Entropy is an important energetic quantity determining the progression of chemical processes. We propose a new approach to obtain hydration entropy directly from probability density functions in state space. We demonstrate the validity of our approach for a series of cations in aqueous solution. Extensive validation of simulation results was performed. Our approach does not make prior assumptions about the shape of the potential energy landscape and is capable of calculating accurate hydration entropy values. Sampling times in the low nanosecond range are sufficient for the investigated ionic systems. Although the presented strategy is at the moment limited to systems for which a scalar order parameter can be derived, this is not a principal limitation of the method. The strategy presented is applicable to any chemical system where sufficient sampling of conformational space is accessible, for example, by computer simulations. more...
- Published
- 2013
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4. Physical interaction of apoptosis-inducing factor with DNA and RNA.
- Author
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Vahsen N, Candé C, Dupaigne P, Giordanetto F, Kroemer RT, Herker E, Scholz S, Modjtahedi N, Madeo F, Le Cam E, and Kroemer G
- Subjects
- Amino Acid Sequence, Apoptosis Inducing Factor chemistry, Brain metabolism, Chromatin Immunoprecipitation, DNA chemistry, DNA genetics, HeLa Cells, Humans, Mass Spectrometry, Microscopy, Electron, Models, Molecular, Molecular Sequence Data, Polymerase Chain Reaction, RNA chemistry, RNA genetics, Apoptosis Inducing Factor metabolism, Chromatin Assembly and Disassembly physiology, DNA metabolism, RNA metabolism
- Abstract
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein, which upon apoptosis induction translocates to the nucleus where it interacts with DNA by virtue of positive charges clustered on the AIF surface. Here we show that the AIF interactome, as determined by mass spectroscopy, contains a large panel of ribonucleoproteins, which apparently bind to AIF through the RNA moiety. However, AIF is devoid of any detectable RNAse activity both in vitro and in vivo. Recombinant AIF can directly bind to DNA as well as to RNA. This binding can be visualized by electron microscopy, revealing that AIF can condense DNA, showing a preferential binding to single-stranded over double-stranded DNA. AIF also binds and aggregates single-stranded and structured RNA in vitro. Single-stranded poly A, poly G and poly C, as well double-stranded A/T and G/C RNA competed with DNA for AIF binding with a similar efficiency, thus corroborating a computer-calculated molecular model in which the binding site within AIF is the same for distinct nucleic acid species, without a clear sequence specificity. Among the preferred electron donors and acceptors of AIF, nicotine adenine dinucleotide phosphate (NADP) was particularly efficient in enhancing the generation of higher-order AIF/DNA and AIF/RNA complexes. Altogether, these data support a model in which a direct interaction of AIF contributes to the compaction of nucleic acids within apoptotic cells. more...
- Published
- 2006
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5. Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor.
- Author
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Weaver JG, Tarze A, Moffat TC, Lebras M, Deniaud A, Brenner C, Bren GD, Morin MY, Phenix BN, Dong L, Jiang SX, Sim VL, Zurakowski B, Lallier J, Hardin H, Wettstein P, van Heeswijk RP, Douen A, Kroemer RT, Hou ST, Bennett SA, Lynch DH, Kroemer G, and Badley AD more...
- Subjects
- Animals, Antibodies administration & dosage, Disease Models, Animal, Female, Hepatitis drug therapy, Hepatitis pathology, Humans, Jurkat Cells, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mitochondrial ADP, ATP Translocases chemistry, Models, Molecular, Nelfinavir pharmacology, Ritonavir pharmacology, Shock, Septic drug therapy, Shock, Septic pathology, Signal Transduction drug effects, Stroke drug therapy, Stroke pathology, Apoptosis drug effects, HIV Protease Inhibitors pharmacology, Mitochondrial ADP, ATP Translocases antagonists & inhibitors
- Abstract
Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B-induced shock, and middle cerebral artery occlusion-induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex. more...
- Published
- 2005
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6. AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis.
- Author
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Candé C, Vahsen N, Kouranti I, Schmitt E, Daugas E, Spahr C, Luban J, Kroemer RT, Giordanetto F, Garrido C, Penninger JM, and Kroemer G
- Subjects
- Apoptosis Inducing Factor, Cell Line, Tumor, Cell Nucleus drug effects, Cell Nucleus metabolism, Culture Media, Serum-Free, Enzyme Inhibitors pharmacology, Green Fluorescent Proteins, HeLa Cells, Humans, Jurkat Cells, Luminescent Proteins metabolism, Mass Spectrometry, Models, Molecular, Recombinant Proteins metabolism, Sequence Deletion, Staurosporine pharmacology, Vimentin metabolism, Apoptosis drug effects, Chromatin metabolism, Cyclophilin A metabolism, Flavoproteins metabolism, Membrane Proteins metabolism
- Abstract
Cyclophilin A (CypA) was determined to interact with apoptosis-inducing factor (AIF) by mass spectroscopy, coimmunoprecipitation, pull-down assays, and molecular modeling. During the initial, caspase-independent stage of chromatin condensation that accompanies apoptosis, AIF and CypA were found to coimmunolocalize in the nucleus. Recombinant AIF and CypA proteins synergized in vitro in the degradation of plasmid DNA, as well as in the capacity to induce DNA loss in purified nuclei. The apoptogenic cooperation between AIF and CypA did not rely on the CypA peptidyl-prolyl cis-trans isomerase activity. In Cyp-expressing cells, AIF overexpression augmented apoptotic chromatinolysis. The AIF-dependent large-scale DNA fragmentation was less pronounced in CypA knockout cells as compared to controls. AIF mutants lacking the CypA-binding domain were inefficient apoptosis sensitizers in transfection experiments. Moreover, AIF failed to sensitize CypA knockout cells to apoptosis induction, and this defect in the AIF response was reversed by reintroduction of the CypA gene into CypA-deficient cells. In summary, AIF and CypA collaborate in chromatinolysis. more...
- Published
- 2004
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- View/download PDF
7. Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant.
- Author
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Schmitt E, Parcellier A, Gurbuxani S, Cande C, Hammann A, Morales MC, Hunt CR, Dix DJ, Kroemer RT, Giordanetto F, Jäättelä M, Penninger JM, Pance A, Kroemer G, and Garrido C
- Subjects
- Apoptosis physiology, Apoptosis Inducing Factor, Caspase 3, Caspase 9, Caspases metabolism, Computer Simulation, Flavoproteins genetics, Green Fluorescent Proteins, HSP70 Heat-Shock Proteins antagonists & inhibitors, Luminescent Proteins biosynthesis, Luminescent Proteins genetics, Membrane Proteins genetics, Models, Molecular, Mutagenesis, Peptide Mapping, Protein Conformation, Protein Structure, Tertiary, Transfection, Flavoproteins metabolism, HSP70 Heat-Shock Proteins metabolism, Membrane Proteins metabolism
- Abstract
Heat shock protein 70 (HSP70) inhibits apoptosis and thereby increases the survival of cells exposed to a wide range of lethal stimuli. HSP70 has also been shown to increase the tumorigenicity of cancer cells in rodent models. The protective function of this chaperone involves interaction and neutralization of the caspase activator apoptotic protease activation factor-1 and the mitochondrial flavoprotein apoptosis-inducing factor (AIF). In this work, we determined by deletional mutagenesis that a domain of AIF comprised between amino acids 150 and 228 is engaged in a molecular interaction with the substrate-binding domain of HSP70. Computer calculations favored this conclusion. On the basis of this information, we constructed an AIF-derived protein, which is cytosolic, noncytotoxic, yet maintains its capacity to interact with HSP70. This protein, designated ADD70, sensitized different human cancer cells to apoptosis induced by a variety of death stimuli by its capacity to interact with HSP70 and therefore to sequester HSP70. Thus, its chemosensitizing effect was lost in cells in which inducible HSP70 genes had been deleted. These data delineate a novel strategy for the selective neutralization of HSP70. more...
- Published
- 2003
8. A three-dimensional model of Suppressor Of Cytokine Signalling 1 (SOCS-1).
- Author
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Giordanetto F and Kroemer RT
- Subjects
- Amino Acid Sequence, Amino Acids genetics, Amino Acids metabolism, Carrier Proteins genetics, Elongin, Janus Kinase 2, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases metabolism, Repressor Proteins chemistry, Repressor Proteins metabolism, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, Structure-Activity Relationship, Substrate Specificity, Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling Proteins, Transcription Factors chemistry, Transcription Factors metabolism, src Homology Domains, Carrier Proteins chemistry, Carrier Proteins metabolism, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins
- Abstract
Suppressor Of Cytokine Signalling 1 (SOCS-1) is one of the proteins responsible for the negative regulation of the JAK-STAT pathway triggered by many cytokines. This important inhibition involves complex formation between SOCS-1 and JAK2, which requires particular structural domains (KIR, ESS and SH2) on SOCS-1. A three-dimensional theoretical model of SOCS-1 is presented here. The model was generated by the application of different modelling techniques, including threading, structure-based modelling, surface analysis and protein docking. The structure accounts for the interactions between SOCS-1 and two other key proteins in the JAK-STAT pathway, namely JAK2 and Elongin BC. The proposed model for the interaction between SOCS-1 and JAK2 suggests that the SOCS-1 suppress the kinase activity of JAK2 by obstructing the catalytic groove of the tyrosine kinase. Subsequent interaction of the JAK-SOCS complex with Elongin BC was also modelled. A sequence and structural comparison between the SH2 domain of SOCS-1 and the SH2 domains of other proteins highlights key residues that could be responsible for SOCS-1 specificity. Currently available mutational data are evaluated. The results are consistent with the experimental data and they provide deeper insights into the inhibitory function of SOCS-1 at a molecular level. more...
- Published
- 2003
- Full Text
- View/download PDF
9. Prediction of the structure of human Janus kinase 2 (JAK2) comprising JAK homology domains 1 through 7.
- Author
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Giordanetto F and Kroemer RT
- Subjects
- Amino Acid Sequence, Computer Simulation, Humans, Janus Kinase 2, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Engineering, Protein Structure, Tertiary, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Sequence Homology, Amino Acid, Static Electricity, Protein-Tyrosine Kinases chemistry, Proto-Oncogene Proteins
- Abstract
A theoretical model of human Janus kinase 2 (JAK2) comprising all seven Janus homology domains is presented. The model was generated by application of homology modelling approaches. The three-dimensional structure contains, starting from the N-terminus, FERM (4.1, ezrin, radixin, moesin), SH2 (Src homology region 2), tyrosine kinase-like, and tyrosine kinase domains. The predicted inter-domain orientation in JAK2 is discussed and the currently existing mutational data for Janus kinases are evaluated. Structural details of the SH2 and the FERM domains are presented. The predictions indicate that the SH2 domain is not fully functional. A number of hydrophobic amino acids of the FERM domain that are predicted to be involved in the constitutive association with the cytokine receptors are highlighted. The model gives new insights into the structure-function relationship of this important protein, and areas that could be investigated by mutation studies are highlighted. more...
- Published
- 2002
- Full Text
- View/download PDF
10. Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation.
- Author
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Lindauer K, Loerting T, Liedl KR, and Kroemer RT
- Subjects
- Amino Acid Sequence, Consensus Sequence, Conserved Sequence, Data Interpretation, Statistical, Enzyme Activation, Homeostasis, Humans, Immunoglobulin Joining Region chemistry, Janus Kinase 2, Models, Molecular, Molecular Sequence Data, Mutation, Protein Kinases chemistry, Protein Structure, Tertiary, Sequence Alignment, Sequence Homology, Amino Acid, Protein-Tyrosine Kinases chemistry, Proto-Oncogene Proteins
- Abstract
The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) was predicted by application of homology modelling techniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-like domains, respectively, and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made and structural differences are highlighted. Prediction of the relative orientation of JH1 and JH2 was aided by a newly developed method for the detection of correlated amino acid mutations. Analysis of the interactions between the two domains led to a model for the regulatory effect of JH2 on JH1. The predictions are consistent with available experimental data on JAK2 or related proteins and provide an explanation for inhibition of JH1 tyrosine kinase activity by the adjacent JH2 domain. more...
- Published
- 2001
- Full Text
- View/download PDF
11. A structural model of the human thrombopoietin receptor complex.
- Author
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Deane CM, Kroemer RT, and Richards WG
- Subjects
- Amino Acid Sequence, Binding Sites, Computer Graphics, Humans, Molecular Sequence Data, Molecular Structure, Proto-Oncogene Proteins metabolism, Receptors, Thrombopoietin, Sequence Alignment, Thrombopoietin metabolism, Models, Molecular, Neoplasm Proteins, Protein Conformation, Proto-Oncogene Proteins chemistry, Receptors, Cytokine, Thrombopoietin chemistry
- Abstract
Thrombopoietin (TPO) is a glycoprotein hormone that regulates red blood cell production. Presented here is a modeling study of the extracellular region of the human thrombopoietin receptor complex, in particular the TPO-receptor interface. The models were developed from structural homology to other cytokines and their receptors. Experimental evidence suggests that the receptor is homodimeric and it was modeled accordingly. Key interactions are shown that correlate with previous cytokine receptor complexes, and the pattern of cysteine bonding (Cys7-Cys151 and Cys29-Cys85) agrees with that experimentally determined for thrombopoietin. These models pave the way for possible mutagenesis experimentation and the design of (ant)agonists. more...
- Published
- 1997
- Full Text
- View/download PDF
12. Homology modeling study of the human interleukin-7 receptor complex.
- Author
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Kroemer RT and Richards WG
- Subjects
- Amino Acid Sequence, Evaluation Studies as Topic, Forecasting, Humans, Molecular Sequence Data, Protein Binding, Protein Conformation, Receptors, Interleukin-7, Reproducibility of Results, Sequence Alignment methods, Antigens, CD chemistry, Computer Simulation, Interleukin-7, Models, Molecular, Receptors, Interleukin chemistry, Sequence Homology, Amino Acid
- Abstract
Following a recent model of human interleukin-7 (IL-7), we present here a modeling study of the extracellular part of the human IL-7 receptor complex, including the IL-7 specific (IL-7R) and the common gamma (gamma c) chains. The investigation is based on structural homology to the complex of human growth hormone (hGH) bound to its receptor (hGHR). For domain 1 of IL-7R two different models are presented which differ in the alignment to hGHR in three regions. However, these differences affect binding to IL-7 in only one region, at the interface between loop EF of domain 1 of IL-7R and helix C of IL-7. The disulfide pattern in domain 1 of IL-7R is predicted to deviate from that observed in hGHR in that the C'-E disulfide (hGHR) is replaced by a C-C' cross-link. The prediction for the gamma c chain is compared with two previous studies. The models of the complex provide insight into the binding of IL-7 to its receptor and have implications for the suggestion of mutagenesis experiments and the design of (ant)agonists. more...
- Published
- 1996
- Full Text
- View/download PDF
13. Prediction of the three-dimensional structure of human interleukin-7 by homology modeling.
- Author
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Kroemer RT, Doughty SW, Robinson AJ, and Richards WG
- Subjects
- Amino Acid Sequence, Animals, Cattle, Cystine analysis, Granulocyte-Macrophage Colony-Stimulating Factor chemistry, Growth Hormone chemistry, Humans, Interleukin-2 chemistry, Interleukin-4 chemistry, Mice, Molecular Sequence Data, Sequence Alignment, Species Specificity, Computer Simulation, Interleukin-7 chemistry, Models, Molecular, Protein Structure, Tertiary
- Abstract
The three-dimensional structure of human interleukin (IL)-7 has been predicted based on homology to human IL-2, IL-4, granulocyte-macrophage colony stimulating factor and growth hormone. The model has a topology common to other cytokines and displays a unique disulfide pattern. Knowledge of the tertiary structure of IL-7 has implications for analysis of key binding regions, suggestions for mutagenesis experiments and design of (ant)agonists. In this context, the model is discussed and compared with other cytokine structures. more...
- Published
- 1996
- Full Text
- View/download PDF
14. A new procedure for improving the predictiveness of CoMFA models and its application to a set of dihydrofolate reductase inhibitors.
- Author
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Kroemer RT and Hecht P
- Subjects
- Computer Simulation, Humans, Molecular Structure, Structure-Activity Relationship, Computer-Aided Design, Drug Design, Folic Acid Antagonists chemistry, Models, Molecular, Protein Conformation, Tetrahydrofolate Dehydrogenase chemistry
- Abstract
A new automated procedure to improve the predictive quality of CoMFA models for both training and test sets is described. A model of greater consistency is generated by performing small reorientations of the underlying molecules for which too low activities are calculated. In order to predict activities of test compounds, the most similar molecules in the previously optimized model are identified and used as a basis for the prediction. This method has been applied to two independent sets of dihydrofolate reductase inhibitors (80 compounds each, serving as training sets), resulting in a significant increase of the cross-validated r2 value. For both models, the predictive r2 value for a test set consisting of 70 compounds was improved substantially. more...
- Published
- 1995
- Full Text
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15. Replacement of steric 6-12 potential-derived interaction energies by atom-based indicator variables in CoMFA leads to models of higher consistency.
- Author
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Kroemer RT and Hecht P
- Subjects
- Electrochemistry, Folic Acid Antagonists chemistry, Molecular Conformation, Molecular Probes, Structure-Activity Relationship, Computer Simulation, Drug Design, Models, Molecular, Thermodynamics
- Abstract
The steric descriptors commonly used in CoMFA--Lennard-Jones 6-12 potential-derived interaction energies calculated between a probe atom and the molecules under investigation--have been replaced by variables indicating the presence of an atom of a particular molecule in predefined volume elements (cubes) within the region enclosing the ensemble of superimposed molecules. The resulting 'atom indicator vectors' were used as steric fields in the subsequent PLS analyses, with and without inclusion of electrostatic Coulomb interaction-derived fields. Application of this method to five training sets (80 compounds each) and five test sets (60 compounds each), randomly selected from an ensemble of 256 dihydrofolate reductase inhibitors, leads to models of significantly higher consistency, as indicated by the cross-validated r2 values for the training sets and the predictive r2 values for the test sets. more...
- Published
- 1995
- Full Text
- View/download PDF
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