PDBsum entry 6iiu

Signaling protein

PDB id: 6iiu

Contents

Protein chain

460 a.a.

Ligands

A8X

CLR

OLC ×2

GOL

Metals

_ZN

Waters ×11

PDB id:

6iiu

Name:

Signaling protein

Title:

Crystal structure of the human thromboxane a2 receptor bound to ramatroban

Structure:

Soluble cytochrome b562,thromboxane a2 receptor,rubredoxin, thromboxane a2 receptor. Chain: a. Synonym: cytochrome b-562,txa2-r,prostanoid tp receptor,rd,txa2-r, prostanoid tp receptor. Engineered: yes. Mutation: yes. Other_details: gpcr protein followed a traditional fusion strategy by introducing a bril fusion protein at the n terminus of the receptor

Source:

Escherichia coli, homo sapiens, clostridium pasteurianum. Human. Organism_taxid: 562, 9606, 1501. Gene: cybc, tbxa2r. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.50Å R-factor: 0.199 R-free: 0.218

Authors:

H.Fan,Q.Zhao,B.Wu

Key ref:

H.Fan et al. (2019). Structural basis for ligand recognition of the human thromboxane A₂ receptor. Nat Chem Biol, 15, 27-33. PubMed id: 30510189 DOI: 10.1038/s41589-018-0170-9

Date:

07-Oct-18 Release date: 19-Dec-18

Protein chain

P00268  (RUBR_CLOPA) -  Rubredoxin from Clostridium pasteurianum

Seq: 54 a.a.

Struc: 460 a.a.

Protein chain

P0ABE7  (C562_ECOLX) -  Soluble cytochrome b562 from Escherichia coli

Seq: 128 a.a.

Struc: 460 a.a.*

Protein chain

P21731  (TA2R_HUMAN) -  Thromboxane A2 receptor from Homo sapiens

Seq: 343 a.a.

Struc: 460 a.a.*

* PDB and UniProt seqs differ at 67 residue positions (black crosses)

DOI no: 10.1038/s41589-018-0170-9

Nat Chem Biol 15:27-33 (2019)

PubMed id: 30510189

Structural basis for ligand recognition of the human thromboxane A₂ receptor.

H.Fan, S.Chen, X.Yuan, S.Han, H.Zhang, W.Xia, Y.Xu, Q.Zhao, B.Wu.

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.