Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1782402654971887616 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4659624 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT rosealexanders roleofstructuraldynamicsatthereceptorgproteininterfaceforsignaltransduction AT zachariaeulrich roleofstructuraldynamicsatthereceptorgproteininterfaceforsignaltransduction AT grubmullerhelmut roleofstructuraldynamicsatthereceptorgproteininterfaceforsignaltransduction AT hofmannklauspeter roleofstructuraldynamicsatthereceptorgproteininterfaceforsignaltransduction AT scheererpatrick roleofstructuraldynamicsatthereceptorgproteininterfaceforsignaltransduction AT hildebrandpeterw roleofstructuraldynamicsatthereceptorgproteininterfaceforsignaltransduction |