白三烯G蛋白偶联受体的结构多样性。

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-12 DOI:10.1016/j.jbc.2023.105247
Aleksandra Luginina, Anastasiia Gusach, Elizaveta Lyapina, Polina Khorn, Nadezda Safronova, Mikhail Shevtsov, Daria Dmitirieva, Dmitrii Dashevskii, Tatiana Kotova, Ekaterina Smirnova, Valentin Borshchevskiy, Vadim Cherezov, Alexey Mishin
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引用次数: 0

摘要

二羟基酸白三烯(LTB4)和半胱氨酸白三酶(LTC4、LTD4和LTE4)是通过5-脂氧合酶途径来源于花生四烯酸的炎症介质。虽然结构相似,但这两种类型的白三烯(LT)通过与两个不同的G蛋白偶联受体(GPCR)家族BLT和CysLT受体的相互作用发挥其功能,这两个家族具有低序列相似性,属于系统发育上不同的GPCR组。LT受体的选择性拮抗已被认为是治疗许多炎症相关疾病的一种有前途的策略,包括哮喘和慢性阻塞性肺病、类风湿性关节炎、囊性纤维化、糖尿病和几种类型的癌症。选择性CysLT1R拮抗剂目前被用作平喘药物,然而,还没有批准的针对CysLT2和BLT受体的药物。在这篇综述中,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整体构象、参与受体激活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的意外结合模式使其成为靶向GPCR的钠结合位点的化合物的第一个实例,并提出了一种新的受体活性调节策略。总之,这些最新的结构数据揭示了两个LT受体家族的分子结构的显著差异,并为用基于结构的药物设计方法获得的新工具化合物选择性靶向单个受体的新治疗策略铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural diversity of leukotriene G-protein coupled receptors.

Structural diversity of leukotriene G-protein coupled receptors.

Structural diversity of leukotriene G-protein coupled receptors.

Structural diversity of leukotriene G-protein coupled receptors.

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 (LTs) 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 LT receptors has been proposed as a promising strategy for the treatment of many inflammation-related diseases including asthma and chronic obstructive pulmonary disease, rheumatoid arthritis, cystic fibrosis, diabetes, and several types of cancer. Selective CysLT1R antagonists are currently used as antiasthmatic 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 LT 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.

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