TY - JOUR
T1 - Structures of the 5-HT 2A receptor in complex with the antipsychotics risperidone and zotepine
AU - Kimura, Kanako Terakado
AU - Asada, Hidetsugu
AU - Inoue, Asuka
AU - Kadji, Francois Marie Ngako
AU - Im, Dohyun
AU - Mori, Chihiro
AU - Arakawa, Takatoshi
AU - Hirata, Kunio
AU - Nomura, Yayoi
AU - Nomura, Norimichi
AU - Aoki, Junken
AU - Iwata, So
AU - Shimamura, Tatsuro
N1 - Funding Information:
We thank K. Yamashita and the beamline staff for helping with the data collection at SPring-8. Data were collected at SPring-8 (Proposal nos. 2013A1379, 2013B1184, 2014A1301, 2014B1273, 2015A1044, 2015A1080, 2015B2080 and 2017A2524). This research was supported by the Information Core of the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and Development (AMED), the Research Acceleration Program of the JST (S.I.), JSPS KAKENHI (grant nos. 24370044, 24121715, 26102725, 15H04338, 17K19349, and 18H02388 (T.S.), 26840021 (K.T.K.) and 17K08264 (A.I.)), the PRIME JP17gm5910013 (A.I.) and the LEAP JP17gm0010004 (A.I. and J.A.) from AMED, and the Mitsubishi Foundation (T.S).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Many drugs target the serotonin 2A receptor (5-HT 2A R), including second-generation antipsychotics that also target the dopamine D 2 receptor (D 2 R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT 2A R in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT 2A R is structurally similar to 5-HT 2C R but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT 2A R-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT 2A R significantly differs around extracellular loops 1 and 2 from that in D 2 R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT 2A R-selective drugs.
AB - Many drugs target the serotonin 2A receptor (5-HT 2A R), including second-generation antipsychotics that also target the dopamine D 2 receptor (D 2 R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT 2A R in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT 2A R is structurally similar to 5-HT 2C R but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT 2A R-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT 2A R significantly differs around extracellular loops 1 and 2 from that in D 2 R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT 2A R-selective drugs.
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U2 - 10.1038/s41594-018-0180-z
DO - 10.1038/s41594-018-0180-z
M3 - Article
C2 - 30723326
AN - SCOPUS:85061146992
VL - 26
SP - 121
EP - 128
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1545-9993
IS - 2
ER -