Journal: Elife / Year: 2023 Title: Cryo-EM structure of the endothelin-1-ET-G complex. Authors: Fumiya K Sano / Hiroaki Akasaka / Wataru Shihoya / Osamu Nureki / Abstract: The endothelin ET receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ET signaling induces reactive astrocytes in the brain and vasorelaxation in ...The endothelin ET receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ET signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle. Consequently, ET 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-G complex at 2.8 Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ET receptor structures revealed how endothelin-1 activates the ET receptor. The NPxxY motif, essential for G-protein activation, is not conserved in ET, resulting in a unique structural change upon G-protein activation. Compared with other GPCR-G-protein complexes, ET binds G 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 agonists.
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