9mbd

Cryo-EM structure of Apo-GPCR

spinqualitylabelsall models 9mbd, resolution 3.32Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mbd is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.32Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GRM8_HUMAN G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. Publication Abstract from PubMed 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(i/o) proteins, the involvement of beta-arrestin is unknown. Here, we found that both mGlu8 agonists and positive allosteric modulators (PAMs) activate G(i) signaling, but mainly agonists induce beta-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(i) protein, and agonist-bound with beta-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(i) protein asymmetrically (2:1), while two beta-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. Structural characterization of five functional states of metabotropic glutamate receptor 8.,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 JP, Yan W, Shao Z, Liu J Mol Cell. 2025 Sep 18;85(18):3460-3473.e6. doi: 10.1016/j.molcel.2025.08.019. PMID:40972528 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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