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X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog
Nature Structural & Molecular Biology ( IF 16.8 ) Pub Date :  , DOI: 10.1038/nsmb.3450
Wataru Shihoya , Tomohiro Nishizawa , Keitaro Yamashita , Asuka Inoue , Kunio Hirata , Francois Marie Ngako Kadji , Akiko Okuta , Kazutoshi Tani , Junken Aoki , Yoshinori Fujiyoshi , Tomoko Doi , Osamu Nureki

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.

中文翻译:

与临床拮抗剂波生坦及其类似物结合的内皮素ET B受体的X射线结构

内皮素受体(ETR)在血管控制中起着至关重要的作用,是设计用于治疗循环系统疾病和癌症进展的药物的靶标。非肽双ETR拮抗剂波生坦是首个被批准用于治疗肺动脉高压的口服药物。在这里,我们报告人内皮素ET B受体的晶体结构分别以3.6-Å和2.2-Å的分辨率与波生坦和ET B选择性类似物K-8794结合。K-8794绑定的结构揭示了跨膜核心的详细的水介导的氢键网络,这可能解释了Na +离子对ET B的弱负变构调节作用。与波生坦结合的结构揭示了与ET B的详细相互作用,可能在ET A受体中是保守的。两种结构的比较显示拮抗剂和激动剂结合之间出乎意料的相似性。尽管存在相似之处,但波生坦在空间上阻止跨膜螺旋6(TM6)向内运动,因此发挥了拮抗作用。这些结构见解将有助于合理设计新的靶向ETR的药物。
更新日期:2017-09-07
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