PDBsum entry 6iiu

Signaling protein

PDB id: 6iiu

Contents

Protein chain

460 a.a.

Ligands

A8X

CLR

OLC ×2

GOL

Metals

_ZN

Waters ×11

References listed in PDB file

Key reference

• Title: Structural basis for ligand recognition of the human thromboxane a₂ receptor.
• Authors: H.Fan, S.Chen, X.Yuan, S.Han, H.Zhang, W.Xia, Y.Xu, Q.Zhao, B.Wu.
• Ref.: Nat Chem Biol, 2019, 15, 27-33. [DOI no: 10.1038/s41589-018-0170-9]
• PubMed id: 30510189

Abstract

Stimulated by thromboxane A₂, an endogenous arachidonic acid metabolite, the thromboxane A₂ receptor (TP) plays a pivotal role in cardiovascular homeostasis, and thus is considered as an important drug target for cardiovascular disease. Here, we report crystal structures of the human TP bound to two nonprostanoid antagonists, ramatroban and daltroban, at 2.5 Å and 3.0 Å resolution, respectively. The TP structures reveal a ligand-binding pocket capped by two layers of extracellular loops that are stabilized by two disulfide bonds, limiting ligand access from the extracellular milieu. These structures provide details of interactions between the receptor and antagonists, which help to integrate previous mutagenesis and SAR data. Molecular docking of prostanoid-like ligands, combined with mutagenesis, ligand-binding and functional assays, suggests a prostanoid binding mode that may also be adopted by other prostanoid receptors. These insights into TP deepen our understanding about ligand recognition and selectivity mechanisms of this physiologically important receptor.