Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

The endothelin ET_Breceptor is a promiscuous G-protein coupled receptor, activated by vasoactive peptide endothelins. ET_Bsignaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle, and thus ET_Bagonists are expected to be utilized for neuroprotection and improved anti-tumor drug delivery. Here, we report a cryo-electron microscopy structure of the endothelin-1-ET_B-G_icomplex at 2.8-Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ET_Breceptor structures revealed how endothelin-1 activates the ET_Breceptor. The NPxxY motif, which is essential for G-protein activation, is not conserved in ET_B, resulting in a unique structural change upon G-protein activation. As Compared with other GPCR-G-protein complexes, ET_Bbinds G_iat the shallowest position, thus expanding the diversity of G-protein binding. This structural information will facilitate the elucidation of G-protein activation and the rational design of ET_B-agonists.