6A93

Crystal structure of 5-HT2AR in complex with risperidone

Summary for 6A93

• Entry DOI: 10.2210/pdb6a93/pdb
• Descriptor: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, 3-[2-[4-(6-fluoranyl-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, CHOLESTEROL, ... (6 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 86493.04

Authors

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. (deposition date: 2018-07-11, release date: 2019-02-13, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3 Å)