X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog
X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog
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DOI：
10.1038/nsmb.3450
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发表时间：
2017-08
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通讯作者：
W. Shihoya;T. Nishizawa;K. Yamashita;A. Inoue;K. Hirata;Francois Marie Ngako Kadji;Akiko Okuta;K. Tani;J. Aoki;Y. Fujiyoshi;T. Doi;O. Nureki
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作者：
W. Shihoya;T. Nishizawa;K. Yamashita;A. Inoue;K. Hirata;Francois Marie Ngako Kadji;Akiko Okuta;K. Tani;J. Aoki;Y. Fujiyoshi;T. Doi;O. Nureki
内皮素受体（ETR）在血管控制中起着至关重要的作用，是治疗循环系统疾病和癌症进展的药物的靶点。非肽类双ETR拮抗剂波生坦是第一个被批准用于治疗肺动脉高压的口服药物。在这里，我们报告的晶体结构的人内皮素ETB受体结合波生坦和ETB选择性类似物K-8794，在3.6-<$N和2.2-<$N分辨率分别。K-8794结合的结构揭示了在跨膜核心处详细的水介导的氢键网络，这可以解释Na+离子对ETB的弱负变构调节。波生坦结合结构揭示了与ETB的详细相互作用，这可能在ETA受体中是保守的。两种结构的比较显示了拮抗剂和激动剂结合之间出乎意料的相似性。尽管存在这种相似性，波生坦在空间上阻止跨膜螺旋6（TM 6）的向内移动，从而发挥其拮抗活性。这些结构的见解将有助于合理设计新的ETR靶向药物。
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 ETBreceptor 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 ETBby Na+ions. The bosentan-bound structure reveals detailed interactions with ETB, which are probably conserved in the ETAreceptor. 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.