title: Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction.
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.
authors.affiliation: Institute of Medical Physics and Biophysics (CC2), Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.|Team ProteiInformatics, Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Rose
authors.affiliation: Dep. of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, 37077, Göttingen, Germany.|Computational Biology, School of Life Sciences, and Physics, School of Science and Engineering, University of Dundee, Dow Street, Dundee, DD1 5EH, United Kingdom.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zachariae
authors.affiliation: Dep. of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grubmüller
authors.affiliation: Institute of Medical Physics and Biophysics (CC2), Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.|Centre of Biophysics and Bioinformatics, Humboldt-Universität zu Berlin, Invalidenstrasse 42, 10115, Berlin, Germany.
authors.forename: Klaus Peter
authors.initials: KP
authors.lastname: Hofmann
authors.affiliation: Institute of Medical Physics and Biophysics (CC2), Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.|Team Protein X-ray Crystallography and Signal Transduction, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Scheerer
authors.affiliation: Institute of Medical Physics and Biophysics (CC2), Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.|Team ProteiInformatics, Universitätsmedizin Berlin, Charitéplatz 1, 10098, Berlin, Germany.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
mesh_terms: D006153:Guanosine Diphosphate / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D006153:Guanosine Diphosphate; D020962:Heterotrimeric GTP-Binding Proteins