Open AccessRole of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction
Author(s) -
Alexander Rose,
Ulrich Zachariae,
Helmut Grubmüller,
Klaus Peter Hofmann,
Patrick Scheerer,
Peter W. Hildebrand
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0143399
Subject(s) - heterotrimeric g protein , docking (animal) , g protein , chemistry , protein structure , hydrogen–deuterium exchange , g protein coupled receptor , molecular dynamics , hydrogen bond , biophysics , stereochemistry , protein subunit , crystallography , signal transduction , biology , biochemistry , molecule , mass spectrometry , computational chemistry , medicine , nursing , organic chemistry , chromatography , gene
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.