Activation mechanism of endothelin ETB receptor by endothelin-1

Nature. 2016 Sep 15;537(7620):363-368. doi: 10.1038/nature19319. Epub 2016 Sep 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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