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 () and Tatsuro Shimamura ()
Additional contact information
Dohyun Im: Kyoto University
Asuka Inoue: Tohoku University
Takaaki Fujiwara: Kyoto University
Takanori Nakane: University of Tokyo
Yasuaki Yamanaka: Kyoto University
Tomoko Uemura: Kyoto University
Chihiro Mori: Kyoto University
Yuki Shiimura: Kyoto University
Kanako Terakado Kimura: Kyoto University
Hidetsugu Asada: Kyoto University
Norimichi Nomura: Kyoto University
Tomoyuki Tanaka: Kyoto University
Ayumi Yamashita: Kyoto University
Eriko Nango: RIKEN SPring-8 Center
Kensuke Tono: Japan Synchrotron Radiation Research Institute
Francois Marie Ngako Kadji: Tohoku University
Junken Aoki: Tohoku University
So Iwata: Kyoto University
Tatsuro Shimamura: Kyoto University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20221-0

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DOI: 10.1038/s41467-020-20221-0

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