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

Nairie Michaelian, Anastasiia Sadybekov, Élie Besserer-Offroy, Gye Won Han, Harini Krishnamurthy, Beata A. Zamlynny, Xavier Fradera, Phieng Siliphaivanh, Jeremy Presland, Kerrie B. Spencer, Stephen M. Soisson, Petr Popov, Philippe Sarret, Vsevolod Katritch and Vadim Cherezov ()
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Nairie Michaelian: University of Southern California
Anastasiia Sadybekov: University of Southern California
Élie Besserer-Offroy: Université de Sherbrooke
Gye Won Han: 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
Philippe Sarret: Université de Sherbrooke
Vsevolod Katritch: University of Southern California
Vadim Cherezov: University of Southern California

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23149-1

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DOI: 10.1038/s41467-021-23149-1

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