内皮素ETB受体是一种多面手G蛋白偶联受体，可被血管活性肽内皮素激活。ETB信号诱导大脑反应性星形胶质细胞和血管平滑肌松弛。因此，ETB激动剂预计将用于神经保护和改善抗肿瘤药物传递。在这里，我们报道了内皮素-1-ETB-Gi复合物的2.8Å分辨率的冷冻电子显微镜结构，并通过新建立的方法稳定了复合物组装。与非活性ETB受体结构的比较揭示了内皮素-1如何激活ETB受体。NPxxY基序对于G蛋白激活是必不可少的，但在ETB中并未保守，因此在G蛋白激活时产生了独特的结构变化。与其他GPCR-G蛋白复合物相比，ETB以最浅的位置结合Gi，进一步扩大了G蛋白结合模式的多样性。这些结构信息将有助于阐明G蛋白的激活和合理设计ETB激动剂。©2023年，Sano等人。

The endothelin ETB receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ETB signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle. Consequently, ETB agonists are expected to be drugs for neuroprotection and improved anti-tumor drug delivery. Here, we report the cryo-electron microscopy structure of the endothelin-1-ETB-Gi complex at 2.8 Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ETB receptor structures revealed how endothelin-1 activates the ETB receptor. The NPxxY motif, essential for G-protein activation, is not conserved in ETB, resulting in a unique structural change upon G-protein activation. Compared with other GPCR-G-protein complexes, ETB binds Gi in the shallowest position, further expanding the diversity of G-protein binding modes. This structural information will facilitate the elucidation of G-protein activation and the rational design of ETB agonists.© 2023, Sano et al.