# Structural and dynamic insights into agonist recognition and function of the thromboxane A2 receptor

## TL;DR

This study reveals the structure and activation mechanism of the thromboxane A2 receptor, offering insights into its role in blood clotting and disease.

## Contribution

The paper presents novel structural and dynamic insights into TP activation and agonist recognition using Gq-bound receptor structures.

## Key findings

- The TP has a unique activation switch differing from typical class A GPCRs.
- Agonist and antagonist binding mechanisms differ significantly.
- A molecular gate formed by transmembrane helices facilitates ligand entry.

## Abstract

The thromboxane A2 receptor (TP), expressed in platelets and smooth muscle, plays an important role in blood clotting and muscle contraction. The endogenous ligand of this G protein-coupled receptor (GPCR), thromboxane A2 (TXA2), is a short-lived arachidonic acid metabolite with a half-life of ∼30 seconds, which makes investigating the TP structure and activation mechanism highly challenging. Here we determine the structures of the TP in complex with the synthetic agonists, U46619 and I-BOP, stable analogues of the natural ligand, in the presence of the signalling protein partner, Gq. The structures reveal a unique activation switch for the receptor that differs from typical class A GPCR family members. Complemented by functional studies, mutational analysis, docking, and molecular dynamics (MD) simulations, our investigation highlights the differences between agonist and antagonist binding and explores the ligand entry mechanism to the binding pocket from within the membrane via a molecular gate composed of two transmembrane helices. In addition, our study provides crucial information to aid in the rational design of compounds targeting the TP, and offers mechanistic insights into inherited disorders associated with mutations in the TP.

The thromboxane A2 receptor (TP) is an important mediator of cardiovascular homeostasis. Here, authors report two structures of active TP-Gq bound to U46619 and I-BOP, revealing a molecular mechanism of TP activation and providing mechanistic insights into disease-associated TP mutations.