A Computational Study of a Recreated G Protein-GEF Reaction Intermediate Competent for Nucleotide Exchange: Fate of the Mg Ion
| Autor: | Charles H. Robert, Mériam Ben Hamida-Rebaï |
|---|---|
| Přispěvatelé: | Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Protein Conformation G protein Static Electricity Computational Biology/Macromolecular Structure Analysis lcsh:Medicine Biochemistry/Biocatalysis Small G Protein Reaction intermediate Molecular Dynamics Simulation Computational Biology/Molecular Dynamics 010402 general chemistry Guanosine Diphosphate 01 natural sciences Protein–protein interaction 03 medical and health sciences Protein structure GTP-binding protein regulators GTP-Binding Proteins Biochemistry/Cell Signaling and Trafficking Structures Guanine Nucleotide Exchange Factors Humans Magnesium [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] lcsh:Science 030304 developmental biology Molecular switch 0303 health sciences Multidisciplinary Molecular Structure Nucleotides lcsh:R 0104 chemical sciences Energy Transfer Models Chemical Biochemistry Biophysics Biophysics/Biomacromolecule-Ligand Interactions ADP-Ribosylation Factor 1 lcsh:Q Guanosine Triphosphate Guanine nucleotide exchange factor Algorithms Research Article Protein Binding |
| Zdroj: | PLoS ONE PLoS ONE, Public Library of Science, 2010, 5 (2), pp.e9142. ⟨10.1371/journal.pone.0009142⟩ PLoS ONE, Vol 5, Iss 2, p e9142 (2010) |
| ISSN: | 1932-6203 |
| Popis: | International audience; Small G-proteins of the superfamily Ras function as molecular switches, interacting with different cellular partners according to their activation state. G-protein activation involves the dissociation of bound GDP and its replacement by GTP, in an exchange reaction that is accelerated and regulated in the cell by guanine-nucleotide exchange factors (GEFs). Large conformational changes accompany the exchange reaction, and our understanding of the mechanism is correspondingly incomplete. However, much knowledge has been derived from structural studies of blocked or inactive mutant GEFs, which presumably closely represent intermediates in the exchange reaction and yet which are by design incompetent for carrying out the nucleotide exchange reaction. In this study we have used comparative modelling to recreate an exchange-competent form of a late, pre-GDP-ejection intermediate species in Arf1, a well-characterized small G-protein. We extensively characterized three distinct models of this intermediate using molecular dynamics simulations, allowing us to address ambiguities related to the mutant structural studies. We observed in particular the unfavorable nature of Mg 2z associated forms of the complex and the establishment of closer Arf1-GEF contacts in its absence. The results of this study shed light on GEF-mediated activation of this small G protein and on predicting the fate of the Mg ion at a critical point in the exchange reaction. The structural models themselves furnish additional targets for interfacial inhibitor design, a promising direction for exploring potentially druggable targets with high biological specificity. |
| Databáze: | OpenAIRE |
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