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Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity

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    Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity
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    † ‡ †Institut für Medizinische Physik und Biophysik, ‡AG ProteiInformatics, and #AG Protein X-ray Crystallography, Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
    § Division of Computational Biology, College of Life Sciences, and Division of Physics, School of Engineering, Physics and Mathematics, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
    ∥ Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, D-37077 Göttingen, Germany
    ⊥ Centre of Biophysics and Bioinformatics, Humboldt-Universität zu Berlin, Invalidenstrasse 42, D-10115 Berlin, Germany
    [email protected]
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    Cite this: J. Am. Chem. Soc. 2014, 136, 32, 11244–11247
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    https://doi.org/10.1021/ja5055109
    Published July 21, 2014
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    G protein coupled receptors (GPCRs) transmit extracellular signals into the cell by binding and activating different intracellular signaling proteins, such as G proteins (Gαβγ, families Gi, Gs, Gq, G12/13) or arrestins. To address the issue of Gs vs Gi coupling specificity, we carried out molecular dynamics simulations of lipid-embedded active β2-adrenoceptor (β2AR*) in complex with C-terminal peptides derived from the key interaction site of Gα (GαCT) as surrogate of Gαβγ. We find that GiαCT and GsαCT exploit distinct cytoplasmic receptor conformations that coexist in the uncomplexed β2AR*. The slim GiαCT stabilizes a β2AR* conformation, not accessible to the bulkier GsαCT, which requires a larger TM6 outward tilt for binding. Our results suggest that the TM6 conformational heterogeneity regulates the catalytic activity of β2AR* toward Gi or Gs.

    Copyright © 2014 American Chemical Society

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    Preparation and execution of MD simulations and US calculations, performed and analyzed with GROMACS; GPCRs were selected on the basis of the availability of an X-ray structure of a receptor G protein (or peptides derived thereof) complex, which is a prerequisite for sufficiently accurate atomistic simulations. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 90 publications.

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    Cite this: J. Am. Chem. Soc. 2014, 136, 32, 11244–11247
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