Cysteinyl leukotriene receptor 2 (CysLT2R) has recently become a "rising star" in drug development due to its unique tissue distribution and physiological functions. Recently, a collaborative team led by Zhang Shuyang, President of PUMCH, and Luan Xiaodong, Director of the Drug Development and Evaluation Platform, working with researchers from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, resolved the structure of CysLT2R. They revealed for the first time the structural basis of its activation by cysteinyl leukotriene D4 (LTD4), providing important theoretical foundation for new drug development. This research was recently published in the leading international journal Proceedings of the National Academy of Sciences of the United States of America.
In recent years, as biomedical research has deepened, researchers have increasingly recognized the important roles that cysteinyl leukotriene receptors (CysLTRs) play in inflammatory diseases and cancer. Though CysLT1R and CysLT2R, the two subtypes, belong to the same family, their "workplaces" and “responsibilities” differ significantly. CysLT1R is widely present in lungs, peripheral blood leukocytes, spleen, placenta and other tissues, primarily responsible for “handling” respiratory-related matters, which makes it an important target for treating asthma and allergic rhinitis. CysLT2R, however, prefers the heart, brain, and adrenal glands, involved in cardiovascular, nervous system, and immune system regulation. Its presence has even been detected in cancer pathways and demonstrates significant associations with coronary heart disease, hypertension, heart failure, and arrhythmia.
▲Cysteinyl leukotriene receptor 2 (CysLT2R) in active state
LTD4 is the "preferred ligand" of CysLT1R and is highly active in inflammatory diseases like asthma. It's a key factor in triggering acute and chronic asthma. In disease processes leading to heart failure, such as myocardial infarction and cardiomyopathy, elevated LTD4 levels exacerbate myocardial cell damage and apoptosis, further decreasing myocardial contractility. Currently, several anti-asthma drugs targeting CysLT1R are in clinical use. However, due to insufficient understanding of CysLT2R's activation mechanism, no drugs specifically targeting CysLT2R have been marketed to date.
To explore CysLT2R's activation mechanism, the research team modified human CysLT2R to "collaborate" with Gαq protein in insect cells. They then employed cryo-electron microscopy to successfully resolve the structure of the cysteinyl leukotriene D4 (LTD4)-bound human CysLT2R in complex with a Gαq protein, adopting an active conformation at a resolution of 3.15 ?. This structure reveals how CysLT2R recognizes and binds to LTD4, and how it couples with Gαq protein to transmit signals after activation. Luan Xiaodong explained that this is like opening a door to the microscopic world, making the "interaction" between CysLT2R and LTD4 fully visible.
In addition, the research team used NanoBiT labeling to enhance the stability and homogeneity of the complex and achieved high-resolution structural analysis using cryo-electron microscopy. These technical approaches also provide valuable reference for structural studies of other G protein-coupled receptors (GPCRs).
This study reveals for the first time the high-resolution structure of CysLT2R bound to LTD4 and the interaction mechanism with Gαq protein during activation. It fills the gap in understanding CysLT2R's activation mechanism, provides new clues for the pathogenesis of related diseases, and offers important theoretical foundation for drug development targeting CysLT2R.
Dr. Luan Xiaodong emphasized that ongoing advances in CysLT2R-targeted drug research are likely to yield promising new therapeutics, offering fresh treatment possibilities and hope for patients.
Paper link: https://www.pnas.org/doi/epub/10.1073/pnas.2417148122
Written by Luan Xiaodong and Chen Xiao