9mb9
Cryo-EM structure of Gi-bound GPCR
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedMetabotropic 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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