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; Vadim Cherezov

doi:10.1038/s41467-021-23149-1

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

Nat Commun. 2021 May 20;12(1):2971. doi: 10.1038/s41467-021-23149-1.

Authors

Nairie Michaelian^{1

2}, Anastasiia Sadybekov^{1

2}, Élie Besserer-Offroy^{3

4}, Gye Won Han^{1

2}, Harini Krishnamurthy⁵, Beata A Zamlynny⁵, Xavier Fradera⁵, Phieng Siliphaivanh⁵, Jeremy Presland⁵, Kerrie B Spencer⁵, Stephen M Soisson⁵, Petr Popov^{6

7}, Philippe Sarret³, Vsevolod Katritch^{1

2

8}, Vadim Cherezov^{9

10

11}

Affiliations

¹ Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA.
² Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
³ Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada.
⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
⁵ Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
⁶ Center for Computational and Data Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Moscow, Russia.
⁷ Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
⁸ Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
⁹ Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA. cherezov@usc.edu.
¹⁰ Department of Chemistry, University of Southern California, Los Angeles, CA, USA. cherezov@usc.edu.
¹¹ Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia. cherezov@usc.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Binding Sites / genetics
Crystallography, X-Ray
Diabetes Mellitus, Type 2
HEK293 Cells
Humans
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use
Ligands
Molecular Docking Simulation
Mutagenesis, Site-Directed
Receptors, Leukotriene B4 / agonists
Receptors, Leukotriene B4 / antagonists & inhibitors
Receptors, Leukotriene B4 / genetics
Receptors, Leukotriene B4 / ultrastructure*
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Recombinant Proteins / ultrastructure
Sf9 Cells
Spodoptera
Structure-Activity Relationship

Substances

Hypoglycemic Agents
LTB4R protein, human
Ligands
Receptors, Leukotriene B4
Recombinant Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding