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Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction

GPCRs catalyze GDP/GTP exchange in the α-subunit of heterotrimeric G proteins (Gαßγ) through displacement of the Gα C-terminal α5 helix, which directly connects the interface of the active receptor (R*) to the nucleotide binding pocket of G. Hydrogen–deuterium exchange mass spectrometry and kinetic...

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Autores principales: Rose, Alexander S., Zachariae, Ulrich, Grubmüller, Helmut, Hofmann, Klaus Peter, Scheerer, Patrick, Hildebrand, Peter W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659624/
https://www.ncbi.nlm.nih.gov/pubmed/26606751
http://dx.doi.org/10.1371/journal.pone.0143399
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author Rose, Alexander S.
Zachariae, Ulrich
Grubmüller, Helmut
Hofmann, Klaus Peter
Scheerer, Patrick
Hildebrand, Peter W.
author_facet Rose, Alexander S.
Zachariae, Ulrich
Grubmüller, Helmut
Hofmann, Klaus Peter
Scheerer, Patrick
Hildebrand, Peter W.
author_sort Rose, Alexander S.
collection PubMed
description GPCRs catalyze GDP/GTP exchange in the α-subunit of heterotrimeric G proteins (Gαßγ) through displacement of the Gα C-terminal α5 helix, which directly connects the interface of the active receptor (R*) to the nucleotide binding pocket of G. Hydrogen–deuterium exchange mass spectrometry and kinetic analysis of R* catalysed G protein activation have suggested that displacement of α5 starts from an intermediate GDP bound complex (R*•G(GDP)). To elucidate the structural basis of receptor-catalysed displacement of α5, we modelled the structure of R*•G(GDP). A flexible docking protocol yielded an intermediate R*•G(GDP) complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R*•G(empty)), however with the α5 C-terminus (GαCT) forming different polar contacts with R*. Starting molecular dynamics simulations of GαCT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of α5 with R* in R*•G(empty). The observed rotation of α5 by 60° is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the α5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the α5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket.
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spelling pubmed-46596242015-12-02 Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction Rose, Alexander S. Zachariae, Ulrich Grubmüller, Helmut Hofmann, Klaus Peter Scheerer, Patrick Hildebrand, Peter W. PLoS One Research Article GPCRs catalyze GDP/GTP exchange in the α-subunit of heterotrimeric G proteins (Gαßγ) through displacement of the Gα C-terminal α5 helix, which directly connects the interface of the active receptor (R*) to the nucleotide binding pocket of G. Hydrogen–deuterium exchange mass spectrometry and kinetic analysis of R* catalysed G protein activation have suggested that displacement of α5 starts from an intermediate GDP bound complex (R*•G(GDP)). To elucidate the structural basis of receptor-catalysed displacement of α5, we modelled the structure of R*•G(GDP). A flexible docking protocol yielded an intermediate R*•G(GDP) complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R*•G(empty)), however with the α5 C-terminus (GαCT) forming different polar contacts with R*. Starting molecular dynamics simulations of GαCT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of α5 with R* in R*•G(empty). The observed rotation of α5 by 60° is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the α5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the α5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket. Public Library of Science 2015-11-25 /pmc/articles/PMC4659624/ /pubmed/26606751 http://dx.doi.org/10.1371/journal.pone.0143399 Text en © 2015 Rose et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Rose, Alexander S.
Zachariae, Ulrich
Grubmüller, Helmut
Hofmann, Klaus Peter
Scheerer, Patrick
Hildebrand, Peter W.
Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
title Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
title_full Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
title_fullStr Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
title_full_unstemmed Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
title_short Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
title_sort role of structural dynamics at the receptor g protein interface for signal transduction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659624/
https://www.ncbi.nlm.nih.gov/pubmed/26606751
http://dx.doi.org/10.1371/journal.pone.0143399
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