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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Guanosine Diphosphate / metabolism
  • Heterotrimeric GTP-Binding Proteins / chemistry
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Models, Molecular*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Conformation*
  • Receptors, Adrenergic, beta-2 / chemistry
  • Receptors, Adrenergic, beta-2 / metabolism
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction


  • Receptors, Adrenergic, beta-2
  • Receptors, G-Protein-Coupled
  • Guanosine Diphosphate
  • Heterotrimeric GTP-Binding Proteins

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft Sfb740 (to K.P.H., P.S. and P.W.H.), Sfb1078-B6 (to P.S.), DFG HI 1502/1-1 (to P.W.H.), BI 893/8 (to P.W.H.), DFG Cluster of Excellence ‘Unifying Concepts in Catalysis’ (Research Field D3/E3-1 to P.S.) and ERC Advanced grant (ERC-2009/249910—TUDOR to K.P.H.). The computer time necessary for this project was provided in part by the “Norddeutscher Verbund fuür Hoch und Hoüchstleistungsrechner” (HLRN). U.Z. acknowledges funding from the Scottish Universities Physics Alliance and the UK National Physical Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.