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

ABSTRACT: GPCRs catalyze GDP/GTP exchange in the ?-subunit of heterotrimeric G proteins (G?ß?) through displacement of the G? C-terminal ?5 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 ?5 starts from an intermediate GDP bound complex (R*•GGDP). To elucidate the structural basis of receptor-catalysed displacement of ?5, 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 ?5 C-terminus (G?CT) forming different polar contacts with R*. Starting molecular dynamics simulations of G?CT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of ?5 with R* in R*•Gempty. The observed rotation of ?5 by 60° is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the ?5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the ?5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket.

SUBMITTER: Rose AS 

PROVIDER: S-EPMC4659624 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature