Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4

• 成果类型: Article
• 署名作者: Jiang, Mengting; Xu, Youwei; Luan, Xiaodong; Wu, Kai; Li, Zhen; Xu, H. Eric; Zhang, Shuyang; Jiang, Yi; Yin, Wanchao
• 署名单位: Lingang Laboratory; ShanghaiTech University; Nanjing University of Chinese Medicine; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College Hospital; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12713
• DOI: 10.1073/pnas.2417148122
• 发表日期: 2025-04-15
• 关键词: focal cerebral-ischemia; hami 3379; brain-injury; antagonist; cyslt2r; SYSTEM; cells

摘要

The G protein-coupled cysteinyl leukotriene receptor CysLT2R plays intricate roles in the physiology and pathogenesis of inflammation-related processes. It has garnered increasing attention as a potential therapeutic target for atopic asthma, brain injury, central nervous system disorders, and various types of cancer. In this study, we present the cryo-electron microscopy structure of the cysteinyl leukotriene D4 (LTD4)-bound human CysLT2R in complex with a G alpha q protein, adopting an active conformation at a resolution of 3.15 & Aring;. The structure elucidates a spacious polar pocket designed to accommodate the two branched negative ends of LTD4 and reveals a lateral ligand access route into the orthosteric pocket located on transmembrane domain helix (TM) 4 and 5. Furthermore, our findings highlight the crucial role of transmembrane domain helix 3 in sensing agonist moieties, representing the pivotal mechanism of receptor activation for both CysLT1R and CysLT2R. Collectively, the insights derived from our structural investigation establish a foundation for comprehending CysLT2R activation by its endogenous ligand LTD4, offering a rational basis for the design of drugs targeting CysLT2R.