6IIV

Crystal structure of the human thromboxane A2 receptor bound to daltroban

Summary for 6IIV

• Entry DOI: 10.2210/pdb6iiv/pdb
• Descriptor: Soluble cytochrome b562,Thromboxane A2 receptor,Rubredoxin,Thromboxane A2 receptor, 2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]ethanoic acid, ZINC ION, ... (5 entities in total)
• Functional Keywords: gpcr, complex, antagonist, signaling protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 1
• Total formula weight: 54140.22

Authors

Fan, H.,Zhao, Q.,Wu, B. (deposition date: 2018-10-07, release date: 2018-12-19, Last modification date: 2024-10-16)

Primary citation

Fan, H.,Chen, S.,Yuan, X.,Han, S.,Zhang, H.,Xia, W.,Xu, Y.,Zhao, Q.,Wu, B.
Structural basis for ligand recognition of the human thromboxane A2receptor.
Nat. Chem. Biol., 15:27-33, 2019

PubMed Abstract: Stimulated by thromboxane A, an endogenous arachidonic acid metabolite, the thromboxane A 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.

PubMed: 30510189
DOI: 10.1038/s41589-018-0170-9

Experimental method

X-RAY DIFFRACTION (3 Å)