Cryo-EM structure of the endothelin-1-ETB-Gi complex

Abstract

The endothelin ETB receptor is a promiscuous G-protein coupled receptor, activated by vasoactive peptide endothelins. ETB signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle, and thus ETB agonists 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-ETB-Gi complex at 2.8-[A] 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, which is essential for G-protein activation, is not conserved in ETB, resulting in a unique structural change upon G-protein activation. As Compared with other GPCR-G-protein complexes, ETB binds Gi at 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 ETB-agonists.