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
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 and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 2
ER -