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TitleInsights into the Activation Mechanism of HCA1, HCA2, and HCA3.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 4, Page 4527-4539, Year 2025
Publish dateFeb 27, 2025
AuthorsJiening Wang / Yuxia Qian / Zhen Han / Yize Wang / Yanru Liu / Jie Li / Qingmiao Duanmu / Sheng Ye / Anna Qiao / Shan Wu /
PubMed AbstractHydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on HCA2, its clinical application has been ...Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on HCA2, its clinical application has been limited by adverse effects. Therefore, the role of HCA1 as a promising target for the treatment of lipolysis warrants further exploration. As HCAs exhibit high similarity when activated with diverse selective agonists, a conserved yet unique activation mechanism for HCAs remains undisclosed. Herein, we unveil the cryo-electron microscopy structures of the 3,5-DHBA-HCA1-Gi signaling complex, the acifran- and MK6892-bound HCA2-Gi signaling complexes, and the acifran-HCA3-Gi signaling complex. Comparative analysis across HCAs reveals key residues in HCA1 contributing to the stabilization of the ligand-binding pocket. Furthermore, chimeric complexes and mutational analyses identify residues that are pivotal for HCA2 and HCA3 selectivity. Our findings elucidate critical structural insights into the mechanisms of ligand recognition and activation within HCA1 and broaden our comprehension of ligand specificity binding across the HCA family.
External linksJ Med Chem / PubMed:39936872 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.01 Å
Structure data

62557

9kt6

EMDB-62557, PDB-9kt6:
HCA3-Gi complex with acifran
Method: EM (single particle) / Resolution: 3.01 Å

62558

9kt7

EMDB-62558, PDB-9kt7:
Cryo-EM structure of HCA2-Gi complex with MK6892
Method: EM (single particle) / Resolution: 2.8 Å

62559

9kt8

EMDB-62559, PDB-9kt8:
Cryo-EM structure of HCA2-Gi complex with acifran
Method: EM (single particle) / Resolution: 2.73 Å

62560

9kt9

EMDB-62560, PDB-9kt9:
Cryo-EM structure of HCA1-Gi complex with 3,5-DHBA
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-P9X:
(5~{S})-5-methyl-4-oxidanylidene-5-phenyl-furan-2-carboxylic acid / agonist*YM

ChemComp-FI7:
2-[[2,2-dimethyl-3-[3-(5-oxidanylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic acid

ChemComp-34D:
3,5-DIHYDROXYBENZOATE

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / cryo-EM; G-protein-coupled receptors; Hydroxycarboxylic acid receptors / SIGNALING PROTEIN/IMMUNE SYSTEM / SIGNALING PROTEIN-IMMUNE SYSTEM complex / G-protein-coupled receptors; Hydroxycarboxylic acid receptors / cryo-EM; SIGNALING PROTEIN

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