9JKY

acifran-HCAR2-Gi complex

Summary for 9JKY

• Entry DOI: 10.2210/pdb9jky/pdb
• EMDB information: 61574
• Descriptor: Hydroxycarboxylic acid receptor 2, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (6 entities in total)
• Functional Keywords: gpcr complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 144248.86

Authors

Binghao, Z.,Fang, Y. (deposition date: 2024-09-17, release date: 2025-10-29, Last modification date: 2026-05-13)

Primary citation

Ye, F.,Zhang, Z.,Zhang, B.,Li, X.,Deng, J.,Miao, Q.,Ning, P.,Chi, Y.,Chen, G.,Wu, Z.,Wang, Q.,Xu, L.,Gong, N.,Cheng, B.,Ma, Z.,Qian, C.,Zhu, L.,Pan, X.,Du, Y.
Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity.
Plos Biol., 23:e3003480-e3003480, 2025

PubMed Abstract: The hydroxycarboxylic acid receptors (HCAR2 and HCAR3), also known as prototypical metabolite-sensing receptors, are key targets for treating dyslipidemia and metabolic disorders. While HCAR2 activation, but not HCAR3 activation, is associated with side effects of cutaneous flushing, the structural features and ligand preferences of HCAR3 remain less understood. Here, we used Sf9 cells to express HCAR3-Gi and HCAR2-Gi complexes, and present cryo-EM structures of HCAR3-Gi complexes with agonists compound 6O (3.31 Å), D-phenyllactic acid (3.05 Å), IBC293 (3.26 Å), and acifran (3.18Å), as well as HCAR2-Gi complex with agonist acifran (2.72 Å). Our findings reveal the mechanism behind 6O's highest affinity to HCAR3, attributed to its full occupation of both R1 and R2 regions of the orthosteric binding pocket. Moreover, combined with cAMP assay in HEK-293 cells, we have elucidated that the ligand selectivity between HCAR3 and HCAR2 depended on π-π interaction with F1073.32 (L1073.32 in HCAR2) and ligand-binding pocket size difference, facilitated by key residues difference V/L832.60, Y/N862.63, and S/W9123.48. Collectively, these structural insights lay the groundwork for developing HCAR3-specific drugs, potentially avoiding HCAR2-induced adverse effects.

PubMed: 41359625
DOI: 10.1371/journal.pbio.3003480

Experimental method

ELECTRON MICROSCOPY (2.72 Å)