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Structure paper

TitleStructural insights into the human niacin receptor HCA2-G signalling complex.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1692, Year 2023
Publish dateMar 27, 2023
AuthorsYang Yang / Hye Jin Kang / Ruogu Gao / Jingjing Wang / Gye Won Han / Jeffrey F DiBerto / Lijie Wu / Jiahui Tong / Lu Qu / Yiran Wu / Ryan Pileski / Xuemei Li / Xuejun Cai Zhang / Suwen Zhao / Terry Kenakin / Quan Wang / Raymond C Stevens / Wei Peng / Bryan L Roth / Zihe Rao / Zhi-Jie Liu /
PubMed AbstractThe hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. ...The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-G signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.
External linksNat Commun / PubMed:36973264 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 3.1 Å
Structure data

33241

7xk2

EMDB-33241, PDB-7xk2:
Cryo-EM Structure of Human Niacin Receptor HCA2-Gi protein complex
Method: EM (single particle) / Resolution: 3.1 Å

PDB-7zl9:
Crystal structure of human GPCR Niacin receptor (HCA2)
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

PDB-7zly:
Crystal structure of human GPCR Niacin receptor (HCA2) expressed from Spodoptera frugiperda
Method: X-RAY DIFFRACTION / Resolution: 2.7 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-OLA:
OLEIC ACID / Oleic acid

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER / Diethylene glycol

ChemComp-UNX:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Niacin receptor / hydroxycarboxylic acid receptor 2 / HCA2 / Gi complex / GPCR / membrane protein structure

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