Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA.
Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
Nat Commun. 2021 May 20;12(1):2971. doi: 10.1038/s41467-021-23149-1.
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.
白三烯 B4 受体 1（BLT1）调节不同细胞类型的募集和趋化作用，并在感染、过敏、代谢和致瘤性人类疾病的病理生理学中发挥作用。在这里，我们展示了与人 BLT1（hBLT1）复合物的晶体结构，该复合物与一种选择性拮抗剂 MK-D-046 结合，该拮抗剂是为治疗 2 型糖尿病和其他炎症疾病而开发的。对结构和结构-活性关系数据的综合分析，加上定点突变和对接研究的支持，揭示了配体结合的分子决定因素以及对不同 BLT 受体亚型和种属的选择性。该结构有助于确定一个潜在的膜埋入的配体进入通道以及内源性激动剂的潜在受体结合模式。hBLT1 的这些结构见解丰富了我们对其配体识别的理解，并为基于结构的药物设计开辟了未来的途径。
