9MB9

Cryo-EM structure of Gi-bound GPCR

This is a non-PDB format compatible entry.

Summary for 9MB9

• Entry DOI: 10.2210/pdb9mb9/pdb
• EMDB information: 63770
• Descriptor: Metabotropic glutamate receptor 8, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: complex, protein, antagonist, membrane, membrane protein-immune system complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 290404.56

Authors

Zhao, J.,Zhao, C.,Sun, H.,Shao, Z.H. (deposition date: 2025-03-15, release date: 2025-10-01)

Primary citation

Zhao, J.,Deng, Y.,Xu, Z.,Xu, C.,Zhao, C.,Li, Z.,Sun, H.,Tian, X.,Song, Y.,Cimadevila, M.,Wang, H.,Liu, Y.,Zhang, X.,Chen, Y.,Sun, S.,Yong, X.,Su, L.,He, Y.,Zhong, Y.,Yang, H.,Pin, J.P.,Yan, W.,Shao, Z.,Liu, J.
Structural characterization of five functional states of metabotropic glutamate receptor 8.
Mol.Cell, 85:3460-3473.e6, 2025

PubMed Abstract: Metabotropic glutamate receptors (mGluRs) are dimeric class C G protein-coupled receptors, which play crucial roles in brain physiology and pathology. Among them, mGlu8 is the least characterized, though it is physiologically important. While recognized to signal via G proteins, the involvement of β-arrestin is unknown. Here, we found that both mGlu8 agonists and positive allosteric modulators (PAMs) activate G signaling, but mainly agonists induce β-arrestin recruitment. We solved five human mGlu8 cryo-electron microscopy (cryo-EM) structures in various states: apo, antagonist-bound, agonist + PAM-bound, agonist + PAM-bound with G protein, and agonist-bound with β-arrestin1 states. They revealed a unique PAM-binding pocket at the extracellular side of the TM6/TM7 interface. Agonist and PAM promote active mGlu8 association with one G protein asymmetrically (2:1), while two β-arrestin1 can interact symmetrically (2:2) to both subunits of an inactive dimer state to promote constitutive internalization. These findings elucidate how mGlu8 selectively engages transducers, offering insights into its signaling capabilities and selective drug development.

PubMed: 40972528
DOI: 10.1016/j.molcel.2025.08.019

Experimental method

ELECTRON MICROSCOPY (2.97 Å)