Cryo-EM structure of the endothelin-1-ETB-Gicomplex

Abstract

AbstractThe endothelin ETBreceptor is a promiscuous G-protein coupled receptor, activated by vasoactive peptide endothelins. ETBsignaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle, and thus ETBagonists 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-Gicomplex at 2.8-Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ETBreceptor structures revealed how endothelin-1 activates the ETBreceptor. 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, ETBbinds Giat 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.