Activation and signaling mechanism revealed by GPR119-G<sub>s</sub> complex structures.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36396650.
- Also identified by DOI 10.1038/s41467-022-34696-6 and PMC identifier 9671963.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>s</sub> 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<sub>s</sub>. Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gβ<sub>s</sub> 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.
Medical subject headings
- Signal Transduction
- Receptors, G-Protein-Coupled