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

Dohyun Im, Asuka Inoue, Takaaki Fujiwara, Takanori Nakane, Yasuaki Yamanaka, Tomoko Uemura, Chihiro Mori, Yuki Shiimura, Kanako Terakado Kimura, Hidetsugu Asada, Norimichi Nomura, Tomoyuki Tanaka, Ayumi Yamashita, Eriko Nango, Kensuke Tono, Francois Marie Ngako Kadji, Junken Aoki, So Iwata, Tatsuro Shimamura

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number6442
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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