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Publication Abstract from PubMed

Agonists selectively targeting cannabinoid receptor-like G-protein-coupled receptor (GPCR) GPR119 hold promise for treating metabolic disorders while avoiding unwanted side effects. Here we present the cryo-electron microscopy (cryo-EM) structures of the human GPR119-G(s) signaling complexes bound to AR231453 and MBX-2982, two representative agonists reported for GPR119. The structures reveal a one-amino acid shift of the conserved proline residue of TM5 that forms an outward bulge, opening up a hydrophobic cavity between TM4 and TM5 at the middle of the membrane for its endogenous ligands-monounsaturated lipid metabolites. In addition, we observed a salt bridge between ICL1 of GPR119 and Gbeta(s). Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gbeta(s) in GPR119-mediated signaling. Our structures, together with mutagenesis studies, illustrate the conserved binding mode of the chemically different agonists, and provide insights into the conformational changes in receptor activation and G protein coupling.

Activation and signaling mechanism revealed by GPR119-G(s) complex structures.,Qian Y, Wang J, Yang L, Liu Y, Wang L, Liu W, Lin Y, Yang H, Ma L, Ye S, Wu S, Qiao A Nat Commun. 2022 Nov 17;13(1):7033. doi: 10.1038/s41467-022-34696-6. PMID:36396650^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.