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

Abstract

The endothelin ET_B receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ET_B signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle. Consequently, ET_B 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-ET_B-G_i complex at 2.8 Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ET_B receptor structures revealed how endothelin-1 activates the ET_B receptor. The NPxxY motif, essential for G-protein activation, is not conserved in ET_B, resulting in a unique structural change upon G-protein activation. Compared with other GPCR-G-protein complexes, ET_B binds G_i 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 ET_B agonists.

Keywords: Cryo-EM; Endothelin; GPCR; human; molecular biophysics; structural biology.