7WCM

Cryo-EM structure of GPR119-Gs Complex with small molecule agonist MBX-2982

Summary for 7WCM

• Entry DOI: 10.2210/pdb7wcm/pdb
• EMDB information: 32424
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 144814.96

Authors

Qiao, A.N.,Wu, S.,Ye, S. (deposition date: 2021-12-20, release date: 2022-12-21, Last modification date: 2024-11-06)

Primary citation

Qian, Y.,Wang, J.,Yang, L.,Liu, Y.,Wang, L.,Liu, W.,Lin, Y.,Yang, H.,Ma, L.,Ye, S.,Wu, S.,Qiao, A.
Activation and signaling mechanism revealed by GPR119-G s complex structures.
Nat Commun, 13:7033-7033, 2022

PubMed Abstract: 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 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 Gβ. Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gβ 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.

PubMed: 36396650
DOI: 10.1038/s41467-022-34696-6

Experimental method

ELECTRON MICROSCOPY (2.33 Å)