G-protein activation by a metabotropic glutamate receptor

Alpay B. Seven, Ximena Barros-Álvarez, Marine Lapeyrière, Makaía M. Papasergi-Scott, Michael J. Robertson, Chensong Zhang, Robert M. Nwokonko, Yang Gao, Justin G. Meyerowitz, Jean-Philippe Rocher, Dominik Schelshorn, Brian K. Kobilka (), Jesper M. Mathiesen () and Georgios Skiniotis ()
Additional contact information
Alpay B. Seven: Stanford University School of Medicine
Ximena Barros-Álvarez: Stanford University School of Medicine
Marine Lapeyrière: Addex Therapeutics
Makaía M. Papasergi-Scott: Stanford University School of Medicine
Michael J. Robertson: Stanford University School of Medicine
Chensong Zhang: Stanford University School of Medicine
Robert M. Nwokonko: Stanford University School of Medicine
Yang Gao: Stanford University School of Medicine
Justin G. Meyerowitz: Stanford University School of Medicine
Jean-Philippe Rocher: Addex Therapeutics
Dominik Schelshorn: Addex Therapeutics
Brian K. Kobilka: Stanford University School of Medicine
Jesper M. Mathiesen: University of Copenhagen
Georgios Skiniotis: Stanford University School of Medicine

Nature, 2021, vol. 595, issue 7867, 450-454

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03680-3

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