Cysteinyl leukotrienes (CysLTs) are potent bronchoconstrictors, playing pivotal roles in inflammatory diseases. These lipid mediators exert their effects by activating two G protein-coupled receptors, CysLT1R and CysLT2R. CysLT1R predominantly functions in lungs, while CysLT2R operates across multiple organ systems. Particularly, the unique presence of CysLT2R in heart, brain, and adrenal glands suggests its involvement in cardiovascular and neurological disorders.
The widespread distribution of CysLT2R positions it as both a local inflammation amplifier and a systemic disease bridge. However, the activated conformation of CysLT2R receptor upon binding to an endogenous ligand remains elusive. The precise molecular details of "ligand-receptor" coupling cannot be elucidated, and there are drug-discovery hurdles characterized by drug-screening blind spot and low hit-rate in identifying potential drugs, hampering the treatment of CysLT2R-related diseases.
In a study published in PNAS on April 7, a research team led by YIN Wanchao from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, JIANG Yi from the Lingang Laboratory, and ZHANG Shuyang from the Peking Union Medical College, obtained a high-resolution structure of CysLT2R binding to endogenous ligand cysteinyl leukotriene D4 (LTD4). This structure exhibits an activated conformation with a resolution range of 3.15 Å, and reveals that CysLT2R binds to LTD4 to recruit downstream Gαq protein.
Using single-particle cryo-electron microscopy, the researchers obtained this high-resolution structure, and made several discoveries based on it.
The researchers found that LTD4 can enter the binding pocket through a vertical transverse channel between transmembrane domain helix (TM) 4 and 5. The polar head of LTD4 is anchored securely by a complex hydrogen-bond network with the receptor's second extracellular loop and transmembrane helices. In contrast, the alkyl tail of LTD4 engages in hydrophobic interactions with the receptor, stabilizing the ligand-binding pocket. This "hydrogen-bonding at the top, hydrophobic-locking at the bottom" dual-stabilization mechanism highlights evolutionary conservation in lipid-binding G protein-coupled receptors.
In addition, the researchers revealed that TM3 plays a critical role in inducing agonists and triggering receptor activation. When leukotriene D4 binds to CysLT2R, it triggers a conformational change in TM3, transforming the receptor into its active form and unleashing a cascade of downstream signaling events. Interestingly, in their inactive state, CysLT1R and CysLT2R exhibit almost identical TM3 conformations, suggesting a universal activation "blueprint" for the entire CysLTR family.
This study advances the understanding of how CysLT2R is activated by its endogenous ligand LTD4, which will facilitate the design of structure-based anti-inflammatory and anti-allergic drugs, potentially improving treatment for diseases associated with leukotriene pathway dysregulation. Cardiovascular disease, psychiatric disorders, and certain cancers could benefit from targeted therapies that block CysLT2R, offering new hope for patients suffering from these debilitating conditions.
