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Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation

Author

Listed:
  • Wataru Shihoya

    (The University of Tokyo)

  • Tamaki Izume

    (The University of Tokyo)

  • Asuka Inoue

    (Tohoku University)

  • Keitaro Yamashita

    (The University of Tokyo
    RIKEN SPring-8 Center)

  • Francois Marie Ngako Kadji

    (Tohoku University)

  • Kunio Hirata

    (RIKEN SPring-8 Center)

  • Junken Aoki

    (Tohoku University
    Core Research for Evolutional Science and Technology (AMED-CREST))

  • Tomohiro Nishizawa

    (The University of Tokyo)

  • Osamu Nureki

    (The University of Tokyo)

Abstract

Endothelin receptors (ETA and ETB) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ETB-selective signalling induces vasorelaxation, and thus selective ETB agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ETB receptor in complex with ETB-selective agonist, endothelin-3 and an ETB-selective endothelin analogue IRL1620. The structure of the endothelin-3-bound receptor reveals that the disruption of water-mediated interactions between W6.48 and D2.50 is critical for receptor activation, while these hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure. Consistently, functional analysis reveals the partial agonistic effect of IRL1620. The current findings clarify the detailed molecular mechanism for the coupling between the orthosteric pocket and the G-protein binding, and the partial agonistic effect of IRL1620, thus paving the way for the design of improved agonistic drugs targeting ETB.

Suggested Citation

  • Wataru Shihoya & Tamaki Izume & Asuka Inoue & Keitaro Yamashita & Francois Marie Ngako Kadji & Kunio Hirata & Junken Aoki & Tomohiro Nishizawa & Osamu Nureki, 2018. "Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07094-0
    DOI: 10.1038/s41467-018-07094-0
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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. Tobias Benkel & Mirjam Zimmermann & Julian Zeiner & Sergi Bravo & Nicole Merten & Victor Jun Yu Lim & Edda Sofie Fabienne Matthees & Julia Drube & Elke Miess-Tanneberg & Daniela Malan & Martyna Szpako, 2022. "How Carvedilol activates β2-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Chaehee Park & Jinuk Kim & Seung-Bum Ko & Yeol Kyo Choi & Hyeongseop Jeong & Hyeonuk Woo & Hyunook Kang & Injin Bang & Sang Ah Kim & Tae-Young Yoon & Chaok Seok & Wonpil Im & Hee-Jung Choi, 2022. "Structural basis of neuropeptide Y signaling through Y1 receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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