TY - JOUR

T1 - G-protein activation by a metabotropic glutamate receptor

AU - Seven, Alpay B.

AU - Barros-Álvarez, Ximena

AU - de Lapeyrière, Marine

AU - Papasergi-Scott, Makaía M.

AU - Robertson, Michael J.

AU - Zhang, Chensong

AU - Nwokonko, Robert M.

AU - Gao, Yang

AU - Meyerowitz, Justin G.

AU - Rocher, Jean Philippe

AU - Schelshorn, Dominik

AU - Kobilka, Brian K.

AU - Mathiesen, Jesper M.

AU - Skiniotis, Georgios

N1 - Funding Information: Acknowledgements We thank E. Montabana at the Stanford-SLAC cryo-EM facility for support with data collection and J.-P. Aubry of the FACS facility (University of Geneva) for assistance with the FACS experiments. We also thank G. Eskici for discussions and support with coding. This work was supported, in part, by T32GM089626 (J.G.M.), R01 NS092695 (G.S., B.K.K. and J.M.M.) and R01 NS028471 (B.K.K.). B.K.K. is a Chan Zuckerberg Biohub Investigator. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021

Y1 - 2021

N2 - Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism1. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric Gi. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6–TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound Gi can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6–TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.

AB - Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism1. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric Gi. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6–TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound Gi can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6–TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.

U2 - 10.1038/s41586-021-03680-3

DO - 10.1038/s41586-021-03680-3

M3 - Journal article

C2 - 34194039

AN - SCOPUS:85108917640

VL - 595

SP - 450

EP - 454

JO - Nature

JF - Nature

SN - 0028-0836

ER -