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Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

Author

Listed:
  • Yuki Shiimura

    (Kurume University
    Kyoto University)

  • Shoichiro Horita

    (Kyoto University)

  • Akie Hamamoto

    (Kurume University)

  • Hidetsugu Asada

    (Kyoto University)

  • Kunio Hirata

    (RIKEN
    Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO))

  • Misuzu Tanaka

    (Kurume University)

  • Kenji Mori

    (National Cerebral and Cardiovascular Center Research Institute)

  • Tomoko Uemura

    (Kyoto University)

  • Takuya Kobayashi

    (Kyoto University)

  • So Iwata

    (Kyoto University
    Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO))

  • Masayasu Kojima

    (Kurume University)

Abstract

Ghrelin is a gastric peptide hormone with important physiological functions. The unique feature of ghrelin is its Serine 3 acyl-modification, which is essential for ghrelin’s activity. However, it remains to be elucidated why the acyl-modification of ghrelin is necessary for activity. To address these questions, we solved the crystal structure of the ghrelin receptor bound to antagonist. The ligand-binding pocket of the ghrelin receptor is bifurcated by a salt bridge between E124 and R283. A striking feature of the ligand-binding pocket of the ghrelin receptor is a wide gap (crevasse) between the TM6 and TM7 bundles that is rich in hydrophobic amino acids, including a cluster of phenylalanine residues. Mutagenesis analyses suggest that the interaction between the gap structure and the acyl acid moiety of ghrelin may participate in transforming the ghrelin receptor into an active conformation.

Suggested Citation

  • Yuki Shiimura & Shoichiro Horita & Akie Hamamoto & Hidetsugu Asada & Kunio Hirata & Misuzu Tanaka & Kenji Mori & Tomoko Uemura & Takuya Kobayashi & So Iwata & Masayasu Kojima, 2020. "Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17554-1
    DOI: 10.1038/s41467-020-17554-1
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    Cited by:

    1. Heng Liu & Dapeng Sun & Alexander Myasnikov & Marjorie Damian & Jean-Louis Baneres & Ji Sun & Cheng Zhang, 2021. "Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    2. Yatabe, Zenji & Asubar, Joel T., 2021. "Ornstein–Uhlenbeck process in a human body weight fluctuation," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 582(C).
    3. Zhikuan Zhang & Norimichi Nomura & Yukiko Muramoto & Toru Ekimoto & Tomoko Uemura & Kehong Liu & Moeko Yui & Nozomu Kono & Junken Aoki & Mitsunori Ikeguchi & Takeshi Noda & So Iwata & Umeharu Ohto & T, 2022. "Structure of SARS-CoV-2 membrane protein essential for virus assembly," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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