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Orthosteric and allosteric modulation of human HCAR2 signaling complex

Author

Listed:
  • Chunyou Mao

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Mengru Gao

    (Jiangnan University
    Jiangnan University)

  • Shao-Kun Zang

    (Zhejiang University School of Medicine)

  • Yanqing Zhu

    (Zhejiang University School of Medicine)

  • Dan-Dan Shen

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Li-Nan Chen

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Liu Yang

    (Jiangnan University)

  • Zhiwei Wang

    (Jiangnan University)

  • Huibing Zhang

    (Zhejiang University Medical Center)

  • Wei-Wei Wang

    (Zhejiang University Medical Center)

  • Qingya Shen

    (Zhejiang University Medical Center)

  • Yanhui Lu

    (Peking University)

  • Xin Ma

    (Jiangnan University
    Jiangnan University)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine)

Abstract

Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

Suggested Citation

  • Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43537-z
    DOI: 10.1038/s41467-023-43537-z
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    Cited by:

    1. 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.
    2. 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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