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Nat Chem Biol. 2019 Jan;15(1):27-33. doi: 10.1038/s41589-018-0170-9. Epub 2018 Dec 3.

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

Fan H1,2,3,4, Chen S1,2,3, Yuan X1,3, Han S1,2, Zhang H1,2,3, Xia W5, Xu Y1,3, Zhao Q6,7,8,9, Wu B10,11,12,13.

Author information

1
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
3
University of Chinese Academy of Sciences, Beijing, China.
4
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
5
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
6
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaoq@simm.ac.cn.
7
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaoq@simm.ac.cn.
8
University of Chinese Academy of Sciences, Beijing, China. zhaoq@simm.ac.cn.
9
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China. zhaoq@simm.ac.cn.
10
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.
11
University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
12
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.
13
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.

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.

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

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