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Structural insights on ligand recognition at the human leukotriene B4 receptor 1

Author

Listed:
  • Nairie Michaelian

    (University of Southern California
    University of Southern California)

  • Anastasiia Sadybekov

    (University of Southern California
    University of Southern California)

  • Élie Besserer-Offroy

    (Université de Sherbrooke
    University of California at Los Angeles)

  • Gye Won Han

    (University of Southern California
    University of Southern California)

  • Harini Krishnamurthy

    (Merck & Co., Inc.)

  • Beata A. Zamlynny

    (Merck & Co., Inc.)

  • Xavier Fradera

    (Merck & Co., Inc.)

  • Phieng Siliphaivanh

    (Merck & Co., Inc.)

  • Jeremy Presland

    (Merck & Co., Inc.)

  • Kerrie B. Spencer

    (Merck & Co., Inc.)

  • Stephen M. Soisson

    (Merck & Co., Inc.)

  • Petr Popov

    (Skolkovo Institute of Science and Technology
    Moscow Institute of Physics and Technology)

  • Philippe Sarret

    (Université de Sherbrooke)

  • Vsevolod Katritch

    (University of Southern California
    University of Southern California
    University of Southern California)

  • Vadim Cherezov

    (University of Southern California
    University of Southern California
    Moscow Institute of Physics and Technology)

Abstract

The leukotriene B4 receptor 1 (BLT1) regulates the recruitment and chemotaxis of different cell types and plays a role in the pathophysiology of infectious, allergic, metabolic, and tumorigenic human diseases. Here we present a crystal structure of human BLT1 (hBLT1) in complex with a selective antagonist MK-D-046, developed for the treatment of type 2 diabetes and other inflammatory conditions. Comprehensive analysis of the structure and structure-activity relationship data, reinforced by site-directed mutagenesis and docking studies, reveals molecular determinants of ligand binding and selectivity toward different BLT receptor subtypes and across species. The structure helps to identify a putative membrane-buried ligand access channel as well as potential receptor binding modes of endogenous agonists. These structural insights of hBLT1 enrich our understanding of its ligand recognition and open up future avenues in structure-based drug design.

Suggested Citation

  • Nairie Michaelian & Anastasiia Sadybekov & Élie Besserer-Offroy & Gye Won Han & Harini Krishnamurthy & Beata A. Zamlynny & Xavier Fradera & Phieng Siliphaivanh & Jeremy Presland & Kerrie B. Spencer & , 2021. "Structural insights on ligand recognition at the human leukotriene B4 receptor 1," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23149-1
    DOI: 10.1038/s41467-021-23149-1
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    Cited by:

    1. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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