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PLoS One. 2015 Nov 25;10(11):e0143399. doi: 10.1371/journal.pone.0143399. eCollection 2015.

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

Author information

1
Institute of Medical Physics and Biophysics (CC2), Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.
2
Team ProteiInformatics, Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.
3
Dep. of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
4
Computational Biology, School of Life Sciences, and Physics, School of Science and Engineering, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom.
5
Centre of Biophysics and Bioinformatics, Humboldt-Universität zu Berlin, Invalidenstrasse 42, 10115, Berlin, Germany.
6
Team Protein X-ray Crystallography and Signal Transduction, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.

Abstract

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*•GGDP). To elucidate the structural basis of receptor-catalysed displacement of α5, we modelled the structure of R*•GGDP. A flexible docking protocol yielded an intermediate R*•GGDP complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R*•Gempty), 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*•Gempty. 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.

PMID:
26606751
PMCID:
PMC4659624
DOI:
10.1371/journal.pone.0143399
[Indexed for MEDLINE]
Free PMC Article

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