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

文献类型：期刊论文

作者Jiang, Mengting2,3,4; Xu, Youwei5; Luan, Xiaodong6,7; Wu, Kai5; Li, Zhen4; Xu, H. Eric3,4,5,8; Zhang, Shuyang6,7; Jiang, Yi2,3; Yin, Wanchao1,5,8
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2025-04-15
卷号122期号:15页码:9
关键词G protein-coupled receptor cryo-electron microscopy cysteinyl leukotriene receptor2 activation mechanism G alpha q protein coupling
ISSN号0027-8424
DOI10.1073/pnas.2417148122
英文摘要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.
WOS关键词FOCAL CEREBRAL-ISCHEMIA ; HAMI 3379 ; BRAIN-INJURY ; ANTAGONIST ; CYSLT2R ; SYSTEM ; CELLS
资助项目Shanghai Institute of Material Medica ; National Key R&D Program of China[2023YFC3605504] ; National Science Fund for ExcellentYoung Scholars[82122067] ; National Natural Science Foundation of China[32171189] ; National Natural Science Foundation of China[32171187] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; Youth Innovation Promotion Association of CAS[2021278] ; Zhongshan Municipal Bureau of Science and Technology[CXTD2023010] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project ; Lingang Laboratory[LG-GG-202204-01] ; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences[2021-I2M-1-003] ; National High Level Hospital Clinical Research Funding[2022-PUMCH-D-002] ; National High Level Hospital Clinical Research Funding[2022-PUMCH-B-098] ; The 14th Five-Year Key Research and Development Plan, Ministry of Science and Technology[2022YFC2703100] ; High-level new RD institute[2019B090904008] ; High-level Innovative Research Institute[2021B0909050003] ; Department of Science and Technology of Guangdong Province ; Sanofi Scholarship Program
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001471277900001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/317458]  
专题新药研究国家重点实验室
通讯作者Zhang, Shuyang; Jiang, Yi; Yin, Wanchao
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rare Dis, Beijing 100730, Peoples R China
7.Peking Union Med Coll Hosp, Inst Clin Med, Ctr Drug Res & Evaluat, Natl Infrastruct Translat Med, Beijing 100730, Peoples R China
8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Mengting,Xu, Youwei,Luan, Xiaodong,et al. Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2025,122(15):9.
APA Jiang, Mengting.,Xu, Youwei.,Luan, Xiaodong.,Wu, Kai.,Li, Zhen.,...&Yin, Wanchao.(2025).Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122(15),9.
MLA Jiang, Mengting,et al."Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122.15(2025):9.

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来源：上海药物研究所

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