X-ray crystallographic analyses of human serotonin receptors for structure-based drug discovery.

2016 Fiscal Year Final Research Report

• Project/Area Number: 26840021
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Structural biochemistry
• Research Institution: Kyoto University
• Principal Investigator: Kimura Kanako 京都大学, 医学研究科, 特定研究員 (40726204)
• Research Collaborator: SHIMAMURA Tatsuro 京都大学, 大学院医学研究科, 特定講師 (90391979)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: ヒト膜タンパク質 / X線結晶構造解析

Outline of Final Research Achievements

The purpose of this research is to understand the ligand-selectivity of human serotonin receptors that are targets of antidepressants and atypical antipsychotics. In this study, the crystal structure of serotonin1B receptor bound to a candidate compound of antidepressant, GR127935, was solved at 3.2 Å resolution and that of serotonin2A receptor bound to an antipsychotic drug, risperidone, was solved at 2.7 Å resolution. These two serotonin receptors had different ligand-binding modes. The ligand binding pocket of serotonin1B receptor was shallower than that of serotonin2A receptor. GR127935 had specific interaction with the transmembrane domain in serotonin1B receptor. The binding pocket of serotonin2A receptor had a cavity that is not observed serotonin1B receptor. These results provided a substantial information for understanding ligand selectivity, thereby helping development of safer and more effective medications that target serotonin receptors.

Free Research Field

構造生物学