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TitleStructural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2.
Journal, issue, pagesCell Discov, Vol. 9, Issue 1, Page 118, Year 2023
Publish dateNov 28, 2023
AuthorsXin Pan / Fang Ye / Peiruo Ning / Zhiyi Zhang / Xinyu Li / Binghao Zhang / Qian Wang / Geng Chen / Wei Gao / Chen Qiu / Zhangsong Wu / Jiancheng Li / Lizhe Zhu / Jiang Xia / Kaizheng Gong / Yang Du /
PubMed AbstractHydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply ...Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R111, S179, and Y284. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.
External linksCell Discov / PubMed:38012147 / PubMed Central
MethodsEM (single particle)
Resolution2.69 - 3.28 Å
Structure data

35463

8ij3

EMDB-35463, PDB-8ij3:
Cryo-EM structure of human HCAR2-Gi complex without ligand (apo state)
Method: EM (single particle) / Resolution: 3.28 Å

35483

8ija

EMDB-35483, PDB-8ija:
Cryo-EM structure of human HCAR2-Gi complex with niacin
Method: EM (single particle) / Resolution: 2.69 Å

35484

8ijb

EMDB-35484, PDB-8ijb:
Cryo-EM structure of human HCAR2-Gi complex with acipimox
Method: EM (single particle) / Resolution: 3.23 Å

35485

8ijd

EMDB-35485, PDB-8ijd:
Cryo-EM structure of human HCAR2-Gi complex with MK-6892
Method: EM (single particle) / Resolution: 3.25 Å

Chemicals

ChemComp-NIO:
NICOTINIC ACID

ChemComp-OJX:
5-methyl-4-oxidanyl-pyrazin-4-ium-2-carboxylic acid

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

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / complex

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