6A94

Crystal structure of 5-HT2AR in complex with zotepine

6A94 の概要

• エントリーDOI: 10.2210/pdb6a94/pdb
• 分子名称: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, 2-(3-chloranylbenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethyl-ethanamine, CHOLESTEROL, ... (7 entities in total)
• 機能のキーワード: receptor, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86215.78

構造登録者

Kimura, T.K.,Asada, H.,Inoue, A.,Kadji, F.M.N.,Im, D.,Mori, C.,Arakawa, T.,Hirata, K.,Nomura, Y.,Nomura, N.,Aoki, J.,Iwata, S.,Shimamura, T. (登録日: 2018-07-11, 公開日: 2019-02-13, 最終更新日: 2024-10-23)

主引用文献

Kimura, K.T.,Asada, H.,Inoue, A.,Kadji, F.M.N.,Im, D.,Mori, C.,Arakawa, T.,Hirata, K.,Nomura, Y.,Nomura, N.,Aoki, J.,Iwata, S.,Shimamura, T.
Structures of the 5-HT2Areceptor in complex with the antipsychotics risperidone and zotepine.
Nat.Struct.Mol.Biol., 26:121-128, 2019

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

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

実験手法

X-RAY DIFFRACTION (2.9 Å)