Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500
Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500
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DOI：
10.1038/s42003-019-0482-7
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发表时间：
2019-06-21
影响因子：
5.9
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
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作者：
Nagiri, Chisae;Shihoya, Wataru;Nureki, Osamu
内皮素受体（ETA和ETB）是由内皮素-1激活的G蛋白偶联受体，参与血压调节。IRL 2500是内皮素-1的C-末端三肽的肽模拟物，并且已被表征为有效的ETB选择性拮抗剂，其具有预防脑水肿的作用。在这里，我们报告的晶体结构的人ETB受体与IRL 2500在2.7 A-分辨率的复合物。该结构揭示了IRL 2500与内皮素-1之间的不同结合模式，并提供了对其ETB选择性的结构见解。值得注意的是，IRL 2500的联苯基渗透到D-2.50附近的跨膜核心中，从而稳定了非活性构象。使用新建立的组成型活性突变体，我们清楚地表明，IRL 2500作为ETB受体的反向激动剂的功能。目前的研究结果将扩大ETR拮抗剂的化学空间，并促进其他A类GPCR的反向激动剂的设计。
Endothelin receptors (ETA and ETB) are G-protein-coupled receptors activated by endothelin-1 and are involved in blood pressure regulation. IRL2500 is a peptide-mimetic of the C-terminal tripeptide of endothelin-1, and has been characterized as a potent ETB-selective antagonist, which has preventive effects against brain edema. Here, we report the crystal structure of the human ETB receptor in complex with IRL2500 at 2.7 A-resolution. The structure revealed the different binding modes between IRL2500 and endothelin-1, and provides structural insights into its ETB-selectivity. Notably, the biphenyl group of IRL2500 penetrates into the transmembrane core proximal to D-2.50, thus stabilizing the inactive conformation. Using the newly-established constitutively active mutant, we clearly demonstrate that IRL2500 functions as an inverse agonist for the ETB receptor. The current findings will expand the chemical space of ETR antagonists and facilitate the design of inverse agonists for other class A GPCRs.