Format

Send to

Choose Destination
Nat Struct Mol Biol. 2019 Feb;26(2):121-128. doi: 10.1038/s41594-018-0180-z. Epub 2019 Feb 4.

Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine.

Author information

1
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
2
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
3
Advanced Research & Development Programs for Medical Innovation (PRIME), Japan Agency for Medical Research and Development (AMED), Chiyoda, Tokyo, Japan.
4
Advanced Research & Development Programs for Medical Innovation (LEAP), AMED, Chiyoda, Tokyo, Japan.
5
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan. s.iwata@mfour.med.kyoto-u.ac.jp.
6
RIKEN SPring-8 Center, Sayo, Hyogo, Japan. s.iwata@mfour.med.kyoto-u.ac.jp.
7
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan. t.shimamura@mfour.med.kyoto-u.ac.jp.

Abstract

Many drugs target the serotonin 2A receptor (5-HT2AR), including second-generation antipsychotics that also target the dopamine D2 receptor (D2R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT2AR 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-HT2AR is structurally similar to 5-HT2CR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT2AR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT2AR significantly differs around extracellular loops 1 and 2 from that in D2R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT2AR-selective drugs.

PMID:
30723326
DOI:
10.1038/s41594-018-0180-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center