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Structure paper

TitleMolecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2.
Journal, issue, pagesCell Rep, Vol. 42, Issue 11, Page 113406, Year 2023
Publish dateNov 28, 2023
AuthorsShengnan Zhu / Qingning Yuan / Xinzhu Li / Xinheng He / Shiyi Shen / Dongxue Wang / Junrui Li / Xi Cheng / Xiaoqun Duan / H Eric Xu / Jia Duan /
PubMed AbstractNiacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. ...Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created. However, the activation mechanism of HCAR2 by niacin and these new agonists is not well understood. Here, we present three cryoelectron microscopy structures of Gi-coupled HCAR2 bound to niacin, MK-6892, and GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced by aromatic amino acid clusters (W91, H161, W188, H189, and F193) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111 and Y284, unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs.
External linksCell Rep / PubMed:37952153
MethodsEM (single particle)
Resolution2.8 - 3.05 Å
Structure data

36005

8j6i

EMDB-36005, PDB-8j6i:
Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound MK-6892
Method: EM (single particle) / Resolution: 2.92 Å

36006

8j6j

EMDB-36006, PDB-8j6j:
Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound with GSK256073
Method: EM (single particle) / Resolution: 2.8 Å

36007

8j6l

EMDB-36007, PDB-8j6l:
Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound niacin
Method: EM (single particle) / Resolution: 3.05 Å

Chemicals

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-OKL:
8-chloranyl-3-pentyl-7H-purine-2,6-dione

ChemComp-NIO:
NICOTINIC ACID / Niacin

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / hydroxycarboxylic acid receptor 2 / GPCR / niacin / MK-6892 / GSK256073 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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