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

doi:10.1038/s41467-020-20221-0

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

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Abstract

In addition to the serotonin 5-HT_2A receptor (5-HT_2AR), 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 (D₂R_ris) and haloperidol (D₂R_hal). Here we describe the structure of human D₂R in complex with spiperone (D₂R_spi). In D₂R_spi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D₂R_ris and D₂R_hal, demonstrating that ECL2 in D₂R is highly dynamic. Moreover, D₂R_spi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D₂R and 5-HT_2AR. Together with D₂R_ris and D₂R_hal, the structural information of D₂R_spi should be of value for designing novel antipsychotics with improved safety and efficacy.

Original language	English
Article number	6442
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20221-0
Publication status	Published - 2020 Dec

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Im, D., Inoue, A., Fujiwara, T., Nakane, T., Yamanaka, Y., Uemura, T., Mori, C., Shiimura, Y., Kimura, K. T., Asada, H., Nomura, N., Tanaka, T., Yamashita, A., Nango, E., Tono, K., Kadji, F. M. N., Aoki, J., Iwata, S., & Shimamura, T. (2020). Structure of the dopamine D₂ receptor in complex with the antipsychotic drug spiperone. Nature Communications, 11(1), Article 6442. https://doi.org/10.1038/s41467-020-20221-0

@article{fb8c35a7b8914b17a50ee7f64e39ad6e,

title = "Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone",

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{\textquoteright}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.",

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

note = "Funding Information: This work was supported by grants from the Research Acceleration Program of the JST (S.I.), the X-ray Free-Electron Laser Priority Strategy Program from MEXT (T.S., S.I.), JSPS KAKENHI (Grant Nos. 24370044, 24121715, 26102725, 15H04338, 17K19349, 18H02388, and 20K21392 to T.S.; Grant No. 15K18376 to D.I.; 17K08264 to A.I.; JP19H05777 to S.I.) and the Mitsubishi Foundation (T.S.). This research was also supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) and the Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED under Grant Numbers JP17am0101070 and JP20am0101079; the PRIME JP17gm5910013 (A.I.) and the LEAP JP17gm0010004 (A.I. and J.A.) from AMED. We thank Kayo Sato, Yuko Sugamura and Ayumi Inoue (Tohoku University) for optimization and technical assistance of the TGFα shedding assay. We thank the Radioisotope Research Center and Medical Research Support Center at the Kyoto University for instrumental support. X-ray crystallographic data were collected at SACLA (Proposal No. 2016B8060, 2017A8019, and 2017B8022). We acknowledge computational support from the SACLA HPC system and the Mini-K supercomputer system. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-20221-0",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Im, D, Inoue, A , Fujiwara, T, Nakane, T, Yamanaka, Y, Uemura, T, Mori, C, Shiimura, Y, Kimura, KT, Asada, H, Nomura, N, Tanaka, T, Yamashita, A, Nango, E, Tono, K, Kadji, FMN, Aoki, J, Iwata, S & Shimamura, T 2020, 'Structure of the dopamine D₂ receptor in complex with the antipsychotic drug spiperone', Nature Communications, vol. 11, no. 1, 6442. https://doi.org/10.1038/s41467-020-20221-0

TY - JOUR

T1 - Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone

AU - Im, Dohyun

AU - Inoue, Asuka

AU - Fujiwara, Takaaki

AU - Nakane, Takanori

AU - Yamanaka, Yasuaki

AU - Uemura, Tomoko

AU - Mori, Chihiro

AU - Shiimura, Yuki

AU - Kimura, Kanako Terakado

AU - Asada, Hidetsugu

AU - Nomura, Norimichi

AU - Tanaka, Tomoyuki

AU - Yamashita, Ayumi

AU - Nango, Eriko

AU - Tono, Kensuke

AU - Kadji, Francois Marie Ngako

AU - Aoki, Junken

AU - Iwata, So

AU - Shimamura, Tatsuro

N1 - Funding Information: This work was supported by grants from the Research Acceleration Program of the JST (S.I.), the X-ray Free-Electron Laser Priority Strategy Program from MEXT (T.S., S.I.), JSPS KAKENHI (Grant Nos. 24370044, 24121715, 26102725, 15H04338, 17K19349, 18H02388, and 20K21392 to T.S.; Grant No. 15K18376 to D.I.; 17K08264 to A.I.; JP19H05777 to S.I.) and the Mitsubishi Foundation (T.S.). This research was also supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) and the Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED under Grant Numbers JP17am0101070 and JP20am0101079; the PRIME JP17gm5910013 (A.I.) and the LEAP JP17gm0010004 (A.I. and J.A.) from AMED. We thank Kayo Sato, Yuko Sugamura and Ayumi Inoue (Tohoku University) for optimization and technical assistance of the TGFα shedding assay. We thank the Radioisotope Research Center and Medical Research Support Center at the Kyoto University for instrumental support. X-ray crystallographic data were collected at SACLA (Proposal No. 2016B8060, 2017A8019, and 2017B8022). We acknowledge computational support from the SACLA HPC system and the Mini-K supercomputer system. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85097936252&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-20221-0

DO - 10.1038/s41467-020-20221-0

M3 - Article

C2 - 33353947

AN - SCOPUS:85097936252

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6442

ER -

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

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