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Structure paper

TitleStructural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3.
Journal, issue, pagesCell Rep, Vol. 43, Issue 11, Page 114895, Year 2024
Publish dateNov 26, 2024
AuthorsFang Ye / Xin Pan / Zhiyi Zhang / Xufu Xiang / Xinyu Li / Binghao Zhang / Peiruo Ning / Aijun Liu / Qinggong Wang / Kaizheng Gong / Jiancheng Li / Lizhe Zhu / Chungen Qian / Geng Chen / Yang Du /
PubMed AbstractHydroxycarboxylic acid receptor 3 (HCAR3), a class A G-protein-coupled receptor, is an important cellular energy metabolism sensor with a key role in the regulation of lipolysis in humans. HCAR3 is ...Hydroxycarboxylic acid receptor 3 (HCAR3), a class A G-protein-coupled receptor, is an important cellular energy metabolism sensor with a key role in the regulation of lipolysis in humans. HCAR3 is deeply involved in many physiological processes and serves as a valuable target for the treatment of metabolic diseases, tumors, and immune diseases. Here, we report four cryoelectron microscopy (cryo-EM) structures of human HCAR3-Gi1 complexes with or without agonists: the endogenous ligand 3-hydroxyoctanoic acid, the drug niacin, the highly subtype-specific agonist compound 5c (4-(n-propyl)amino-3-nitrobenzoic acid), and the apo form. Together with mutagenesis and functional analyses, we revealed the recognition mechanisms of HCAR3 for different agonists. In addition, the key residues that determine the ligand selectivity between HCAR2 and HCAR3 were also illuminated. Overall, these findings provide a structural basis for the ligand recognition, activation, and selectivity and G-protein coupling mechanisms of HCAR3, which contribute to the design of HCAR3-targeting drugs with high efficacy and selectivity.
External linksCell Rep / PubMed:39427321
MethodsEM (single particle)
Resolution2.73 - 3.4 Å
Structure data

EMDB-36186, PDB-8jef:
Cryo-EM Structure of the 3HO-HCAR3-Gi complex
Method: EM (single particle) / Resolution: 2.96 Å

EMDB-36189, PDB-8jei:
Cryo-EM Structure of the compuond 5c-HCAR3-Gi complex
Method: EM (single particle) / Resolution: 2.73 Å

EMDB-61501, PDB-9jic:
Cryo-EM Structure of the apo HCAR3-Gi complex
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-61502, PDB-9jid:
Cryo-EM Structure of the niacin-HCAR3-Gi complex
Method: EM (single particle) / Resolution: 2.78 Å

Chemicals

ChemComp-3HO:
(3S)-3-hydroxyoctanoic acid


ChemComp, No image

ChemComp-CW3:
Unknown entry

ChemComp-NIO:
NICOTINIC ACID / medication*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / complex / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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