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Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

Author

Listed:
  • Manbir Sandhu

    (Beckman Research Institute of the City of Hope
    Center for Data Driven Discovery, St. Jude Children’s Research Hospital)

  • Aaron Cho

    (Research Institute of the McGill University Health Centre)

  • Ning Ma

    (Beckman Research Institute of the City of Hope)

  • Elizaveta Mukhaleva

    (Beckman Research Institute of the City of Hope
    Beckman Research Institute of the City of Hope)

  • Yoon Namkung

    (Research Institute of the McGill University Health Centre)

  • Sangbae Lee

    (Beckman Research Institute of the City of Hope)

  • Soumadwip Ghosh

    (Beckman Research Institute of the City of Hope)

  • John H. Lee

    (Beckman Research Institute of the City of Hope)

  • David E. Gloriam

    (University of Copenhagen)

  • Stéphane A. Laporte

    (Research Institute of the McGill University Health Centre
    McGill University)

  • M. Madan Babu

    (Center for Data Driven Discovery, St. Jude Children’s Research Hospital
    Francis Crick Avenue)

  • Nagarajan Vaidehi

    (Beckman Research Institute of the City of Hope
    Beckman Research Institute of the City of Hope)

Abstract

Recent studies have shown that G protein coupled receptors (GPCRs) show selective and promiscuous coupling to different Gα protein subfamilies and yet the mechanisms of the range of coupling preferences remain unclear. Here, we use Molecular Dynamics (MD) simulations on ten GPCR:G protein complexes and show that the location (spatial) and duration (temporal) of intermolecular contacts at the GPCR:Gα protein interface play a critical role in how GPCRs selectively interact with G proteins. We identify that some GPCR:G protein interface contacts are common across Gα subfamilies and others specific to Gα subfamilies. Using large scale data analysis techniques on the MD simulation snapshots we derive a spatio-temporal code for contacts that confer G protein selective coupling and validated these contacts using G protein activation BRET assays. Our results demonstrate that promiscuous GPCRs show persistent sampling of the common contacts more than G protein specific contacts. These findings suggest that GPCRs maintain contact with G proteins through a common central interface, while the selectivity comes from G protein specific contacts at the periphery of the interface.

Suggested Citation

  • Manbir Sandhu & Aaron Cho & Ning Ma & Elizaveta Mukhaleva & Yoon Namkung & Sangbae Lee & Soumadwip Ghosh & John H. Lee & David E. Gloriam & Stéphane A. Laporte & M. Madan Babu & Nagarajan Vaidehi, 2022. "Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34055-5
    DOI: 10.1038/s41467-022-34055-5
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    Cited by:

    1. Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Kazem Asadollahi & Sunnia Rajput & Lazarus Andrew Zhang & Ching-Seng Ang & Shuai Nie & Nicholas A. Williamson & Michael D. W. Griffin & Ross A. D. Bathgate & Daniel J. Scott & Thomas R. Weikl & Guy N., 2023. "Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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