7k15
From Proteopedia
Crystal structure of the Human Leukotriene B4 Receptor 1 in Complex with Selective Antagonist MK-D-046
Structural highlights
FunctionFLAV_DESVH Low-potential electron donor to a number of redox enzymes.LT4R1_HUMAN Receptor for extracellular ATP > UTP and ADP. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. May be the cardiac P2Y receptor involved in the regulation of cardiac muscle contraction through modulation of L-type calcium currents. Is a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response. Publication Abstract from PubMedThe 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. Structural insights on ligand recognition at the human leukotriene B4 receptor 1.,Michaelian N, Sadybekov A, Besserer-Offroy E, Han GW, Krishnamurthy H, Zamlynny BA, Fradera X, Siliphaivanh P, Presland J, Spencer KB, Soisson SM, Popov P, Sarret P, Katritch V, Cherezov V Nat Commun. 2021 May 20;12(1):2971. doi: 10.1038/s41467-021-23149-1. PMID:34016973[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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