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