9II2

Cryo-EM Structure of the 2:2 Complex of mGlu3 and beta-arrestin1

Summary for 9II2

• Entry DOI: 10.2210/pdb9ii2/pdb
• EMDB information: 60588
• Descriptor: Metabotropic glutamate receptor 3, Beta-arrestin-1, scFv30, ... (6 entities in total)
• Functional Keywords: complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 350174.66

Authors

Wen, T.L.,Du, M.,Yang, X.,Shen, Y.Q. (deposition date: 2024-06-18, release date: 2025-03-05, Last modification date: 2025-03-19)

Primary citation

Wen, T.,Du, M.,Lu, Y.,Jia, N.,Lu, X.,Liu, N.,Chang, S.,Zhang, X.,Shen, Y.,Yang, X.
Molecular basis of beta-arrestin coupling to the metabotropic glutamate receptor mGlu3.
Nat.Chem.Biol., 2025

PubMed Abstract: β-Arrestins (βarrs) mediate the desensitization and internalization of activated G-protein-coupled receptors (GPCRs). The molecular mechanism by which dimeric family C GPCR members recruit arrestins remains elusive. Here we report two structures of metabotropic glutamate receptor subtype 3 (mGlu3) coupled to βarr1, with stoichiometries of 2:1 and 2:2. The L-glutamate-bound mGlu3 dimer adopts an inactive state, with both Venus flytrap domains closed, engaging βarr1 either asymmetrically or symmetrically. The transmembrane domain of the mGlu3 protomer interacts with βarr1 through a binding pocket formed by three intracellular loops and an ordered C-terminal region. Three phosphorylation sites (pS857, pS859 and pT860) on the C-terminal tail of mGlu3 engage the N domain of βarr1. βarr1 stabilizes mGlu3 in an inactive conformation, characterized by a TM3/TM4-TM3/TM4 dimeric interface, previously observed in the negative allosteric modulator-bound structure of mGlu3. Our findings provide important insights into βarr-mediated inactivation of family C GPCRs.

PubMed: 40050438
DOI: 10.1038/s41589-025-01858-8

Experimental method

ELECTRON MICROSCOPY (3.7 Å)