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

• 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
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ヒト膜タンパク質 / X線結晶構造解析 / ヒト膜受容体 / ヒト膜蛋白質

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.

Research Products

• [Journal Article] Membrane protein structure determination by SAD, SIR, or SIRAS phasing in serial femtosecond crystallography using an iododetergent (2016)
  • Author(s): Takanori Nakane, Shinya Hanashima, Mamoru Suzuki, Haruka Saiki, Taichi Hayashi, Keisuke Kakinouchi, Shigeru Sugiyama, Satoshi Kawatake, Shigeru Matsuoka, Nobuaki Matsumori, et al
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 113 Issue: 46 Pages: 13039-13044
  • DOI: 10.1073/pnas.1602531113
  • Peer Reviewed / Open Access
• [Presentation] New Iododetergent for Rapid Experimental Phasing of Membrane Proteins in Serial Femtosecond Crystallography. (2016)
  • Author(s): Takanori Nakane, Kanako Kimura, Eiichi Mizohata et al., (申請者は31人中14番目の共著者)
  • Organizer: 14th Conference of the Asian Crystallographic Association
  • Place of Presentation: ベトナム ハノイ
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] 膜蛋白質のSFXによる迅速位相決定を志向したヨウ素含有界面活性剤の開発 (2016)
  • Author(s): 中根智、花島慎弥、鈴木守、斎木悠、林太一、垣之内啓介、杉山成、川竹悟史、松岡茂、松森信明、南後恵理子、小林淳、島村達郎、木村香菜子、森千寿、国島直樹、菅原道泰、高久陽子、井上茂之、桝田哲哉、保坂俊彰、登野健介、城地保昌、亀島敬、初井宇記、矢橋牧名、井上豪、濡木理、岩田想、村田道雄、溝端栄一
  • Organizer: 日本結晶学会平成28年度年会
  • Place of Presentation: 茨城 水戸
  • Year and Date: 2016-11-17