7K15

Crystal structure of the Human Leukotriene B4 Receptor 1 in Complex with Selective Antagonist MK-D-046

Summary for 7K15

• Entry DOI: 10.2210/pdb7k15/pdb
• Descriptor: Leukotriene B4 receptor 1,Flavodoxin,Leukotriene B4 receptor 1, N-(tert-butylsulfonyl)-4-fluoro-2-{(3S,4R)-4-hydroxy-3-[(pyridin-2-yl)methyl]-3,4-dihydro-2H-1-benzopyran-7-yl}benzamide, SODIUM ION, ... (10 entities in total)
• Functional Keywords: human leukotriene b4 receptor 1, hblt1, blt1, bltr1, ltb4, ltb4r, lt4r1, ltb4r1, mk-d-046, selective antagonist, inflammation, inflammatory disease, type 2 diabetes, g protein-coupled receptor, gpcr, flavodoxin fusion, membrane protein, lcp
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 56140.17

Authors

Michaelian, N.,Han, G.W.,Cherezov, V. (deposition date: 2020-09-07, release date: 2021-02-17, Last modification date: 2024-10-16)

Primary citation

Michaelian, N.,Sadybekov, A.,Besserer-Offroy, E.,Han, G.W.,Krishnamurthy, H.,Zamlynny, B.A.,Fradera, X.,Siliphaivanh, P.,Presland, J.,Spencer, K.B.,Soisson, S.M.,Popov, P.,Sarret, P.,Katritch, V.,Cherezov, V.
Structural insights on ligand recognition at the human leukotriene B4 receptor 1.
Nat Commun, 12:2971-2971, 2021

PubMed 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.

PubMed: 34016973
DOI: 10.1038/s41467-021-23149-1

Experimental method

X-RAY DIFFRACTION (2.88 Å)