通过5-脂氧酶途径，花生四烯酸产生了二羟基酸白三烯（LTB4）和半胱氨酸白三烯（LTC4，LTD4和LTE4），它们都是炎症介质。尽管在结构上相似，这两类白三烯通过与两个不同的G-蛋白偶联受体（GPCR）家族相互作用来发挥其功能，即BLT和CysLT受体，它们在序列相似性上有较低的相似度，属于进化上相互分离的GPCR群。选择性拮抗白三烯受体已被提出作为治疗许多与炎症相关的疾病的有希望的策略，包括哮喘和COPD、类风湿性关节炎、囊性纤维化、糖尿病和多种类型的癌症。目前已经有选择性CysLT1R拮抗剂作为抗哮喘药物使用，然而，还没有针对CysLT2和BLT受体的获批药物。在本综述中，我们重点介绍了最近发表的BLT1R和CysLTR的结构，揭示了这两个受体家族的独特结构特征。X-射线和冷冻电镜数据揭示了它们的总体构型、与激活受体有关的功能基序的差异以及配体结合口袋的细节。BLT1R结构中选择性拮抗剂BIIL260的意外结合方式使其成为G-蛋白偶联受体钠结合位点的首个目标化合物，提示了一种新的调控受体活性的策略。总之，这些最新的结构数据揭示了这两个白三烯受体家族的分子架构上的显著差异，并为通过基于结构的药物设计方法获得针对个体受体的新型工具化合物的选择性靶向治疗策略开辟了道路。 版权所有 © 2023 作者。由Elsevier Inc.出版，保留所有权利。

Dihydroxy acid leukotriene (LTB4) and cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. While structurally similar, these two types of leukotrienes exert their functions through interactions with two distinct G -protein-coupled receptor (GPCR) families, BLT and CysLT receptors, which share low sequence similarity and belong to phylogenetically divergent GPCR groups. Selective antagonism of leukotriene receptors has been proposed as a promising strategy for the treatment of many inflammation-related diseases including asthma and COPD, rheumatoid arthritis, cystic fibrosis, diabetes, and several types of cancer. Selective CysLT1R antagonists are currently used as anti-asthmatic drugs, however, there are no approved drugs targeting CysLT2 and BLT receptors. In this review we highlight recently published structures of BLT1R and CysLTRs revealing unique structural features of the two receptor families. X-ray and cryo-EM data shed light on their overall conformations, differences in functional motifs involved in receptor activation and details of the ligand binding pockets. An unexpected binding mode of the selective antagonist BIIL260 in the BLT1R structure makes it the first example of a compound targeting the sodium binding site of GPCRs and suggests a novel strategy for the receptor activity modulation. Taken together, these recent structural data reveal dramatic differences in the molecular architecture of the two leukotriene receptor families and pave the way to new therapeutic strategies of selective targeting individual receptors with novel tool compounds obtained by the structure-based drug design approach.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.