Molecular insights into ago-allosteric modulation at cysteinyl leukotriene receptor 2

Abstract Cysteinyl leukotriene receptor CysLT2R, which is activated by the endogenous cysteinyl leukotrienes (CysLTs) LTC4, LTD4, and LTE4, has emerged as a potential therapeutic target due to the involvement in various inflammatory diseases. Accumulating evidence indicates that CysLT2R is also involved in the pathogenesis of cardiovascular diseases and contribute to tumor progression in cancer. However, the structural basis underlying the ligand recognition and the receptor activation remains to be elucidated. Here, we present two cryo-electron microscopy (cryo-EM) structures of the human CysLT2R-G q complexes bound to LTC4 and LTD4. CysLTs are characterized as ago-allosteric modulators (ago-PAMs) of CysLT2R. Our structures reveal that CysLTs are recognized by a lipid-facing pocket above intracellular loop 2 (ICL2) near the cytoplasmic side of the receptor. Furthermore, a noncanonical activation mechanism exists between the allosteric binding pocket and the G q -binding site. Our findings provide comprehensive insights into the recognition of CysLTs and G q protein signaling transduction by CysLT2R, which may facilitate rational design of drugs.