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

Author

Listed:
  • Yang Yang

    (ShanghaiTech University
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hye Jin Kang

    (Department of Pharmacology, and NIMH Psychoactive Drug Screening Program University of North Carolina Chapel Hill Medical School
    Sungkyunkwan University)

  • Ruogu Gao

    (Chinese Academy of Sciences
    University of 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
    Duke University)

  • Xuemei Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xuejun Cai Zhang

    (Chinese Academy of Sciences
    University of 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
    University of Chinese Academy of Sciences)

  • Zhi-Jie Liu

    (ShanghaiTech University)

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.

Suggested Citation

  • 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 K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37177-6
    DOI: 10.1038/s41467-023-37177-6
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    2. Manish K. Yadav & Parishmita Sarma & Jagannath Maharana & Manisankar Ganguly & Sudha Mishra & Nashrah Zaidi & Annu Dalal & Vinay Singh & Sayantan Saha & Gargi Mahajan & Saloni Sharma & Mohamed Chami &, 2024. "Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Aslihan Shenol & Ricardo Tenente & Michael Lückmann & Thomas M. Frimurer & Thue W. Schwartz, 2024. "Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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