TY - JOUR

T1 - Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

AU - Sandhu, Manbir

AU - Cho, Aaron

AU - Ma, Ning

AU - Mukhaleva, Elizaveta

AU - Namkung, Yoon

AU - Lee, Sangbae

AU - Ghosh, Soumadwip

AU - Lee, John H.

AU - Gloriam, David E.

AU - Laporte, Stéphane A.

AU - Babu, M. Madan

AU - Vaidehi, Nagarajan

N1 - Funding Information: The authors acknowledge financial support by the NIH National Institute of General Medical Sciences (R01-GM117923, R01-GM097261, N.V.), the UK Medical Research Council (MC_U105185859, M.M.B.), the American Lebanese Syrian Associated Charities (ALSAC, M.S., M.M.B.), the Lundbeck Foundation (R313-2019-526, D.E.G.), the Novo Nordisk Foundation (NNF17OC003126, D.E.G.), and the Canadian Institutes of Health Research (PJT-162368 and PJT-173504, S.A.L.). Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-022-34055-5

DO - 10.1038/s41467-022-34055-5

M3 - Journal article

C2 - 36460632

AN - SCOPUS:85143310323

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 7428

ER -