Activation mechanism of endothelin ETB receptor by endothelin-1.

Abstract

Endothelin, a 21-amino-acid peptide, participates in various physiological processes, such as regulation of vascular tone, humoral homeostasis, neural crest cell development and neurotransmission. Endothelin and its G-protein-coupled receptor are involved in the development of various diseases, such as pulmonary arterial hypertension, and thus are important therapeutic targets. Here we report crystal structures of human endothelin type B receptor in the ligand-free form and in complex with the endogenous agonist endothelin-1. The structures and mutation analysis reveal the mechanism for the isopeptide selectivity between endothelin-1 and -3. Transmembrane helices 1, 2, 6 and 7 move and envelop the entire endothelin peptide, in a virtually irreversible manner. The agonist-induced conformational changes are propagated to the receptor core and the cytoplasmic G-protein coupling interface, and probably induce conformational flexibility in TM6. A comparison with the M2 muscarinic receptor suggests a shared mechanism for signal transduction in class A G-protein-coupled receptors.

• Authors: Wataru Shihoya, Tomohiro Nishizawa, Akiko Okuta, Kazutoshi Tani, Naoshi Dohmae, Yoshinori Fujiyoshi, Osamu Nureki, Tomoko Doi
• Journal: Nature (Nature) Vol. 537 Issue 7620 Pg. 363-368 (09 15 2016) ISSN: 1476-4687 [Electronic] England
• PMID: 27595334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Endothelin-3
• Ligands
• Receptor, Endothelin B
• Receptor, Muscarinic M2

Topics

• Allosteric Regulation
• Allosteric Site
• Cell Membrane (metabolism)
• Crystallography, X-Ray
• Endothelin-1 (chemistry, metabolism, pharmacology)
• Endothelin-3 (chemistry, metabolism)
• Humans
• Ligands
• Models, Molecular
• Protein Conformation
• Receptor, Endothelin B (agonists, chemistry, genetics, metabolism)
• Receptor, Muscarinic M2 (chemistry, metabolism)
• Signal Transduction
• Substrate Specificity