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Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone

Author

Listed:
  • Dohyun Im

    (Kyoto University)

  • Asuka Inoue

    (Tohoku University
    Japan Agency for Medical Research and Development (AMED)
    Advanced Research & Development Programs for Medical Innovation (LEAP), AMED)

  • Takaaki Fujiwara

    (Kyoto University
    Tohoku University)

  • Takanori Nakane

    (University of Tokyo
    MRC Laboratory of Molecular Biology)

  • Yasuaki Yamanaka

    (Kyoto University)

  • Tomoko Uemura

    (Kyoto University)

  • Chihiro Mori

    (Kyoto University)

  • Yuki Shiimura

    (Kyoto University
    Kurume University)

  • Kanako Terakado Kimura

    (Kyoto University)

  • Hidetsugu Asada

    (Kyoto University)

  • Norimichi Nomura

    (Kyoto University)

  • Tomoyuki Tanaka

    (Kyoto University
    RIKEN SPring-8 Center)

  • Ayumi Yamashita

    (Kyoto University
    RIKEN SPring-8 Center)

  • Eriko Nango

    (RIKEN SPring-8 Center
    Tohoku University)

  • Kensuke Tono

    (Japan Synchrotron Radiation Research Institute)

  • Francois Marie Ngako Kadji

    (Tohoku University)

  • Junken Aoki

    (Tohoku University
    Advanced Research & Development Programs for Medical Innovation (LEAP), AMED
    University of Tokyo)

  • So Iwata

    (Kyoto University
    RIKEN SPring-8 Center)

  • Tatsuro Shimamura

    (Kyoto University)

Abstract

In addition to the serotonin 5-HT2A receptor (5-HT2AR), the dopamine D2 receptor (D2R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D2R have been described in complex with the inverse agonists risperidone (D2Rris) and haloperidol (D2Rhal). Here we describe the structure of human D2R in complex with spiperone (D2Rspi). In D2Rspi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D2Rris and D2Rhal, demonstrating that ECL2 in D2R is highly dynamic. Moreover, D2Rspi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D2R and 5-HT2AR. Together with D2Rris and D2Rhal, the structural information of D2Rspi should be of value for designing novel antipsychotics with improved safety and efficacy.

Suggested Citation

  • Dohyun Im & Asuka Inoue & Takaaki Fujiwara & Takanori Nakane & Yasuaki Yamanaka & Tomoko Uemura & Chihiro Mori & Yuki Shiimura & Kanako Terakado Kimura & Hidetsugu Asada & Norimichi Nomura & Tomoyuki , 2020. "Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20221-0
    DOI: 10.1038/s41467-020-20221-0
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    Cited by:

    1. Dohyun Im & Jun-ichi Kishikawa & Yuki Shiimura & Hiromi Hisano & Akane Ito & Yoko Fujita-Fujiharu & Yukihiko Sugita & Takeshi Noda & Takayuki Kato & Hidetsugu Asada & So Iwata, 2023. "Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Dohyun Im & Mika Jormakka & Narinobu Juge & Jun-ichi Kishikawa & Takayuki Kato & Yukihiko Sugita & Takeshi Noda & Tomoko Uemura & Yuki Shiimura & Takaaki Miyaji & Hidetsugu Asada & So Iwata, 2024. "Neurotransmitter recognition by human vesicular monoamine transporter 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Xueqian Peng & Linlin Yang & Zixuan Liu & Siyi Lou & Shiliu Mei & Meiling Li & Zhong Chen & Haitao Zhang, 2022. "Structural basis for recognition of antihistamine drug by human histamine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    4. Sandra Arroyo-Urea & Antonina L. Nazarova & Ángela Carrión-Antolí & Alessandro Bonifazi & Francisco O. Battiti & Jordy Homing Lam & Amy Hauck Newman & Vsevolod Katritch & Javier García-Nafría, 2024. "A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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