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Activation mechanism of endothelin ETB receptor by endothelin-1

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  • Wataru Shihoya

    (Graduate School of Pharmaceutical Sciences, Nagoya University
    Cellular and Structural Physiology Institute, Nagoya University
    Graduate School of Science, The University of Tokyo)

  • Tomohiro Nishizawa

    (Graduate School of Science, The University of Tokyo
    Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, 4-1-8 Honcho)

  • 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
    Cellular and Structural Physiology Institute, Nagoya University)

  • Osamu Nureki

    (Graduate School of Science, The University of Tokyo)

  • Tomoko Doi

    (Graduate School of Science, Kyoto University)

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.

Suggested Citation

  • Wataru Shihoya & Tomohiro Nishizawa & Akiko Okuta & Kazutoshi Tani & Naoshi Dohmae & Yoshinori Fujiyoshi & Osamu Nureki & Tomoko Doi, 2016. "Activation mechanism of endothelin ETB receptor by endothelin-1," Nature, Nature, vol. 537(7620), pages 363-368, September.
    • Handle: RePEc:nat:nature:v:537:y:2016:i:7620:d:10.1038_nature19319
    DOI: 10.1038/nature19319
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    Cited by:

    1. Yujie Ji & Jia Duan & Qingning Yuan & Xinheng He & Gong Yang & Shengnan Zhu & Kai Wu & Wen Hu & Tianyu Gao & Xi Cheng & Hualiang Jiang & H. Eric Xu & Yi Jiang, 2023. "Structural basis of peptide recognition and activation of endothelin receptors," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Tamaki Izume & Ryo Kawahara & Akiharu Uwamizu & Luying Chen & Shun Yaginuma & Jumpei Omi & Hiroki Kawana & Fengjue Hou & Fumiya K. Sano & Tatsuki Tanaka & Kazuhiro Kobayashi & Hiroyuki H. Okamoto & Yo, 2024. "Structural basis for lysophosphatidylserine recognition by GPR34," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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