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

## TL;DR

This study reveals how CysLT2R interacts with CysLTs using cryo-EM structures, offering insights for drug design.

## Contribution

The study presents novel cryo-EM structures of CysLT2R-Gq complexes bound to LTC4 and LTD4.

## Key findings

- CysLTs bind to a lipid-facing pocket near the cytoplasmic side of CysLT2R.
- A noncanonical activation mechanism links the allosteric site and Gq-binding site.
- The structures provide insights into CysLT2R's role in signaling and drug design.

## 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-Gq 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 Gq-binding site. Our findings provide comprehensive insights into the recognition of CysLTs and Gq protein signaling transduction by CysLT2R, which may facilitate rational design of drugs.

Cysteinyl leukotriene receptor CysLT2R can be activated by cysteinyl leukotrienes LTC4, LTD4 and LTE4, and is associated with various inflammatory diseases. Here, authors present cryo-EM structures of CysLT2R-Gq bound to LTC4 and LTD4, which are characterized as ago-allosteric modulators of CysLT2R.