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 () and Zhi-Jie Liu ()
Additional contact information
Yang Yang: ShanghaiTech University
Hye Jin Kang: Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School
Ruogu Gao: Chinese Academy of Sciences
Jingjing Wang: ShanghaiTech University
Gye Won Han: University of Southern California
Jeffrey F. DiBerto: Department of Pharmacology, and NIMH Psychoactive Drug Screening Program 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: Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School
Xuemei Li: Chinese Academy of Sciences
Xuejun Cai Zhang: Chinese Academy of Sciences
Suwen Zhao: ShanghaiTech University
Terry Kenakin: Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School
Quan Wang: Chinese Academy of Sciences
Raymond C. Stevens: ShanghaiTech University
Wei Peng: Guangzhou Laboratory
Bryan L. Roth: Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School
Zihe Rao: Chinese Academy of Sciences
Zhi-Jie Liu: ShanghaiTech University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37177-6

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