7MTQ

CryoEM Structure of Full-Length mGlu2 in Inactive-State Bound to Antagonist LY341495

Summary for 7MTQ

• Entry DOI: 10.2210/pdb7mtq/pdb
• EMDB information: 23994
• Descriptor: Metabotropic glutamate receptor 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (3 entities in total)
• Functional Keywords: metabotropic glutamate receptor 2 (mglu2) (mglur2), family c g protein-coupled receptor (gpcr), heterotrimeric g protein, cryoem structure, membrane protein, membrane protein-antagonist complex, membrane protein/antagonist
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 189014.04

Authors

Seven, A.B.,Barros-Alvarez, X.,Skiniotis, G. (deposition date: 2021-05-13, release date: 2021-07-07, Last modification date: 2025-05-28)

Primary citation

Seven, A.B.,Barros-Alvarez, X.,de Lapeyriere, M.,Papasergi-Scott, M.M.,Robertson, M.J.,Zhang, C.,Nwokonko, R.M.,Gao, Y.,Meyerowitz, J.G.,Rocher, J.P.,Schelshorn, D.,Kobilka, B.K.,Mathiesen, J.M.,Skiniotis, G.
G-protein activation by a metabotropic glutamate receptor.
Nature, 595:450-454, 2021

PubMed 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 mechanism. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G. 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 G 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.

PubMed: 34194039
DOI: 10.1038/s41586-021-03680-3

Experimental method

ELECTRON MICROSCOPY (3.65 Å)