Endothelin is a peptide that acts via two G-protein coupled receptors. ETA mainly causes vasoconstriction. In contrast ETB predominantly acts as a beneficial clearing receptor and by the release of endothelium derived relaxing factors, vasodilatation [1,2]. This paper describes for the first time the crystal structure of the endothelin ETB receptor . To date less than 20 structures of Family A, GPCRs (targets of nearly half of all drugs) have been solved experimentally. The number solved for small peptides ligands are limited to the opioid receptor and the 13 amino acid neurotensin. This manuscript extends information to a much larger 21 amino acid peptide and interestingly demonstrates interaction over a substantial portion of the molecule. The authors propose a model whereby the N-terminal tail and the ECL2 β-sheet of ETB together form a lid-like architecture that covers the orthosteric pocket, predicted to form a very stable complex. This provides one structural explanation for the unusual property of ET-1 in causing long lasting responses. Mutations in ETB in receptors can result in Hirschsprung disease in humans, characterized by an absence of enteric ganglia in the distal colon and a failure of innervation in the gastrointestinal tract . ETB receptor mutations are also associated with lethal white foal syndrome in horses as a result of limiting migration of melanocytes, pigment-producing cells found in hair follicles and skin.
 Guide to PHARMACOLOGY: ETB receptor
 Davenport et al. (2016). Endothelin. Pharmacol Rev. 68:357-418. PMID: 26956245
 Shihoya et al. (2016). Activation mechanism of endothelin ETB receptor by endothelin-1. Nature, 537, 363-368. PMID: 27595334
Comments by Anthony Davenport