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

Yang 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

doi:10.1038/s41467-023-37177-6

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

Nat Commun. 2023 Mar 27;14(1):1692. doi: 10.1038/s41467-023-37177-6.

Authors

Yang Yang^#^{1

2

3}, Hye Jin Kang^#^{4

5}, Ruogu Gao^#^{2

3}, Jingjing Wang¹, Gye Won Han⁶, Jeffrey F DiBerto⁴, Lijie Wu¹, Jiahui Tong¹, Lu Qu¹, Yiran Wu¹, Ryan Pileski^{4

7}, Xuemei Li^{2

3}, Xuejun Cai Zhang^{2

3}, Suwen Zhao¹, Terry Kenakin⁴, Quan Wang², Raymond C Stevens¹, Wei Peng⁸, Bryan L Roth⁹, Zihe Rao^{10

11}, Zhi-Jie Liu¹²

Affiliations

¹ iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
² National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27514, USA.
⁵ Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.
⁶ Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA, 90089, USA.
⁷ Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA.
⁸ Innovation Center for Pathogen Research, Guangzhou Laboratory, Guangzhou, 510320, China. peng_wei@gzlab.ac.cn.
⁹ Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, 27514, USA. bryan_roth@med.unc.edu.
¹⁰ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. raozh@tsinghua.edu.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, 100049, China. raozh@tsinghua.edu.cn.
¹² iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. liuzhj@shanghaitech.edu.cn.

^# Contributed equally.

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-G_i 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy
Humans
Ligands
Niacin* / pharmacology
Receptors, G-Protein-Coupled / metabolism
Signal Transduction

Substances

Niacin
Ligands
Receptors, G-Protein-Coupled