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Nat Struct Mol Biol. 2017 Sep;24(9):758-764. doi: 10.1038/nsmb.3450. Epub 2017 Aug 14.

X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog.

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Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan.
Cellular and Structural Physiology Institute, Nagoya University, Nagoya, Japan.
Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Japan.
RIKEN SPring-8 Center, Sayo, Japan.
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan.
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.


Endothelin receptors (ETRs) have crucial roles in vascular control and are targets for drugs designed to treat circulatory-system diseases and cancer progression. The nonpeptide dual-ETR antagonist bosentan is the first oral drug approved to treat pulmonary arterial hypertension. Here we report crystal structures of human endothelin ETB receptor bound to bosentan and to the ETB-selective analog K-8794, at 3.6-Å and 2.2-Å resolution, respectively. The K-8794-bound structure reveals the detailed water-mediated hydrogen-bonding network at the transmembrane core, which could account for the weak negative allosteric modulation of ETB by Na+ ions. The bosentan-bound structure reveals detailed interactions with ETB, which are probably conserved in the ETA receptor. A comparison of the two structures shows unexpected similarity between antagonist and agonist binding. Despite this similarity, bosentan sterically prevents the inward movement of transmembrane helix 6 (TM6), and thus exerts its antagonistic activity. These structural insights will facilitate the rational design of new ETR-targeting drugs.

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