Structural insights into the human niacin receptor HCA2-Gi signalling complex

DOI: 10.1038/s41467-023-37177-6

Authors: Yang Yang (ShanghaiTech University; Institute of Biophysics, Chinese Academy of Science; University of Chinese Academy of Sciences) , Hye Jin Kang (University of North Carolina Chapel Hill Medical School; Sungkyunkwan University) , Ruogu Gao (Institute of Biophysics, Chinese Academy of Sciences; University of Chinese Academy of Sciences) , Jingjing Wang (ShanghaiTech University) , Gye Won Han (University of Southern California) , Jeffrey F. Diberto (University of North Carolina Chapel Hill Medical School) , Lijie Wu (ShanghaiTech University) , Jiahui Tong (ShanghaiTech University) , Lu Qu (ShanghaiTech University) , Yiran Wu (ShanghaiTech University) , Ryan Pileski (Duke University; University of North Carolina Chapel Hill Medical School) , Xuemei Li (Institute of Biophysics, Chinese Academy of Sciences; University of Chinese Academy of Sciences) , Xuejun Cai Zhang (Institute of Biophysics, Chinese Academy of Sciences; University of Chinese Academy of Sciences) , Suwen Zhao (ShanghaiTech University) , Terry Kenakin (University of North Carolina Chapel Hill Medical School) , Quan Wang (Institute of Biophysics, Chinese Academy of Sciences) , Raymond C. Stevens (ShanghaiTech University) , Wei Peng (Guangzhou Laboratory) , Bryan L. Roth (University of North Carolina Chapel Hill Medical School) , Zihe Rao (Institute of Biophysics, Chinese Academy of Sciences; University of Chinese Academy of Sciences) , Zhi-Jie Liu (ShanghaiTech University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: March 2023

Abstract: 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-Gi 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.

Diamond Keywords: Dyslipidemia

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: BL41XU at Spring-8; SSRF; X06SA at SLS

Added On: 30/03/2023 11:33

Documents:
s41467-023-37177-6.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)