Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4
Year: 2025
Type: article
Abstract: 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 Gα q protein, adopting an active conformation at a resolution of 3.15 Å. 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.
Authors: Mengting Jiang, Youwei Xu, Xiaodong Luan, Kai Wu, Zhen Li, H. Eric Xu, Shuyang Zhang, Yi Jiang, Wanchao Yin
Institutions: Nanjing University of Chinese Medicine, ShanghaiTech University, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, State Key Laboratory of Drug Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, University of Chinese Academy of Sciences
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G3570332828, G4428323830, G6285317778
OpenAlex ID: W4409220148