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Structural basis for ligand recognition of the human thromboxane A2 receptor


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.

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Fig. 1: Overall structures of TP–ramatroban and TP–daltroban complexes.
Fig. 2: Extracellular loops in the structures of lipid receptors in extracellular view.
Fig. 3: Binding modes of ramatroban and daltroban in TP.
Fig. 4: Docking poses of prostanoid-like ligands SQ-29548 and U46619 in TP.

Data availability

Atomic coordinates and structure factor files for the TP–ramatroban and TP–daltroban complex structures have been deposited in the Protein Data Bank (PDB) with accession codes 6IIU and 6IIV, respectively. All other data generated or analyzed during this study are included in this published article and its supplementary information file or are available from the corresponding authors on reasonable request.


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This work was supported by the National Key R&D Program of China 2018YFA0507000 (B.W. and Q.Z.), the Key Research Program of Frontier Sciences, CAS, Grant no. QYZDB-SSW-SMC024 (B.W.) and QYZDB-SSW-SMC054 (Q.Z.), and the National Science Foundation of China grants 31825010 (B.W.) and 81525024 (Q.Z.). We thank R.C. Stevens, K. White, M. Audet and T. James for careful review and scientific feedback on the manuscript. The synchrotron radiation experiments were performed at the BL41XU of SPring-8 with approval of the Japan Synchrotron Radiation Research Institute (proposal no. 2016A2517, 2016A2518, 2016B2517 and 2016B2518). We thank the beamline staff members K. Hasegawa, H. Okumura, N. Mizuno, T. Kawamura and H. Murakami of the BL41XU for help on X-ray data collection.

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Authors and Affiliations



H.F. optimized the construct, developed the purification procedure, purified the TP receptors for crystallization and performed crystallization trials and ligand-binding assays. S.C. performed signaling assays. X.Y. performed molecular docking. S.H. solved the structures. H.Z. collected X-ray diffraction data. W.X. helped to optimize the receptor. Y.X. oversaw molecular docking. B.W. and Q.Z. initiated the project, planned and analyzed experiments, supervised the research and wrote the manuscript with input from all co-authors.

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Correspondence to Qiang Zhao or Beili Wu.

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Fan, H., Chen, S., Yuan, X. et al. Structural basis for ligand recognition of the human thromboxane A2 receptor. Nat Chem Biol 15, 27–33 (2019).

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