Structural basis of peptide recognition and activation of endothelin receptors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36882417.
- Also identified by DOI 10.1038/s41467-023-36998-9 and PMC identifier 9992518.
- 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
Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes-endothelin receptor A (ET<sub>A</sub>R) and B (ET<sub>B</sub>R). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ET<sub>A</sub>R and ET<sub>B</sub>R bound to ET-1 and ET<sub>B</sub>R bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.
Medical subject headings
- Endothelin-1
- Cardiovascular Diseases