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Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution

Author

Listed:
  • Manish K. Yadav

    (Indian Institute of Technology)

  • Parishmita Sarma

    (Indian Institute of Technology)

  • Jagannath Maharana

    (Indian Institute of Technology)

  • Manisankar Ganguly

    (Indian Institute of Technology)

  • Sudha Mishra

    (Indian Institute of Technology)

  • Nashrah Zaidi

    (Indian Institute of Technology)

  • Annu Dalal

    (Indian Institute of Technology)

  • Vinay Singh

    (Indian Institute of Technology)

  • Sayantan Saha

    (Indian Institute of Technology)

  • Gargi Mahajan

    (Indian Institute of Technology)

  • Saloni Sharma

    (Indian Institute of Technology)

  • Mohamed Chami

    (Universität Basel)

  • Ramanuj Banerjee

    (Indian Institute of Technology)

  • Arun K. Shukla

    (Indian Institute of Technology)

Abstract

The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46239-2
    DOI: 10.1038/s41467-024-46239-2
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    1. 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.
    2. Shota Suzuki & Kotaro Tanaka & Kouki Nishikawa & Hiroshi Suzuki & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Chuan Hong & Noel J. Byrne & Beata Zamlynny & Srivanya Tummala & Li Xiao & Jennifer M. Shipman & Andrea T. Partridge & Christina Minnick & Michael J. Breslin & Michael T. Rudd & Shawn J. Stachel & Van, 2021. "Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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