Cryo-EM structure of the endothelin-1-ET<sub>B</sub>-G<sub>i</sub> complex.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37096326.
- Also identified by DOI 10.7554/eLife.85821 and PMC identifier 10129325.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The endothelin ET<sub>B</sub> receptor is a promiscuous G-protein coupled receptor that is activated by vasoactive peptide endothelins. ET<sub>B</sub> signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle. Consequently, ET<sub>B</sub> 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<sub>B</sub>-G<sub>i</sub> complex at 2.8 Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ET<sub>B</sub> receptor structures revealed how endothelin-1 activates the ET<sub>B</sub> receptor. The NPxxY motif, essential for G-protein activation, is not conserved in ET<sub>B</sub>, resulting in a unique structural change upon G-protein activation. Compared with other GPCR-G-protein complexes, ET<sub>B</sub> binds G<sub>i</sub> 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<sub>B</sub> agonists.
Medical subject headings
- Endothelin-1
- Endothelins