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Journal Article

Role of structural dynamics at the receptor G protein interface for signal transduction.

MPS-Authors
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Zachariae,  U.
Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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Grubmüller,  H.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

2240338.pdf
(Publisher version), 2MB

Supplementary Material (public)

2240338_Suppl.PDF
(Supplementary material), 8MB

Citation

Rose, A. S., Zachariae, U., Grubmüller, H., Hofmann, K. P., Scheerer, P., & Hildebrand, W. (2015). Role of structural dynamics at the receptor G protein interface for signal transduction. PLOS One, 10(11): e0143399. doi:10.1371/journal.pone.0143399.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0029-4471-0
Abstract
GPCRs catalyze GDP/GTP exchange in the a-subunit of heterotrimeric G proteins (G alpha beta gamma) through displacement of the G alpha C-terminal alpha 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 a5 starts from an intermediate GDP bound complex (R*center dot G(GDP)). To elucidate the structural basis of receptor-catalysed displacement of alpha 5, we modelled the structure of R*center dot G(GDP). A flexible docking protocol yielded an intermediate R*center dot G(GDP) complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R*center dot G(empty)), however with the alpha 5 C-terminus (G alpha CT) forming different polar contacts with R*. Starting molecular dynamics simulations of G alpha CT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of alpha 5 with R* in R*center dot G(empty). The observed rotation of alpha 5 by 60 degrees is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the alpha 5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the alpha 5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket.