Activation mechanism of endothelin ETB receptor by endothelin-1

Wataru Shihoya, Tomohiro Nishizawa, Akiko Okuta, Kazutoshi Tani, Naoshi Dohmae, Yoshinori Fujiyoshi, Osamu Nureki () and Tomoko Doi ()
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Wataru Shihoya: Graduate School of Pharmaceutical Sciences, Nagoya University
Tomohiro Nishizawa: Graduate School of Science, The University of Tokyo
Akiko Okuta: Cellular and Structural Physiology Institute, Nagoya University
Kazutoshi Tani: Cellular and Structural Physiology Institute, Nagoya University
Naoshi Dohmae: Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science
Yoshinori Fujiyoshi: Graduate School of Pharmaceutical Sciences, Nagoya University
Osamu Nureki: Graduate School of Science, The University of Tokyo
Tomoko Doi: Graduate School of Science, Kyoto University

Nature, 2016, vol. 537, issue 7620, 363-368

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19319

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