Structural insights on ligand recognition at the human leukotriene B4 receptor 1.
Animals
Binding Sites
/ genetics
Crystallography, X-Ray
Diabetes Mellitus, Type 2
HEK293 Cells
Humans
Hypoglycemic Agents
/ chemistry
Ligands
Molecular Docking Simulation
Mutagenesis, Site-Directed
Receptors, Leukotriene B4
/ agonists
Recombinant Proteins
/ genetics
Sf9 Cells
Spodoptera
Structure-Activity Relationship
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 05 2021
20 05 2021
Historique:
received:
10
07
2020
accepted:
16
04
2021
entrez:
21
5
2021
pubmed:
22
5
2021
medline:
2
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34016973
doi: 10.1038/s41467-021-23149-1
pii: 10.1038/s41467-021-23149-1
pmc: PMC8137929
doi:
Substances chimiques
Hypoglycemic Agents
0
LTB4R protein, human
0
Ligands
0
Receptors, Leukotriene B4
0
Recombinant Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2971Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM127086
Pays : United States
Organisme : NIH HHS
ID : S10 OD012289
Pays : United States
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