Research on the molecular basis of conformational dynamics of oncogene product Ras for application to the development of its specific inhibitors

2016 Fiscal Year Final Research Report

• Project/Area Number: 26293026
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kobe University
• Principal Investigator: shima fumi 神戸大学, 科学技術イノベーション研究科, 教授 (60335445)
• Co-Investigator(Kenkyū-buntansha): 田中 成典 神戸大学, その他の研究科, 教授 (10379480) ; 熊坂 崇 公益財団法人高輝度光科学研究センター, その他部局等, 研究員 (30291066) ; 片岡 徹 神戸大学, 医学(系)研究科(研究院), 教授 (40144472) ; 松本 篤幸 神戸大学, 医学(系)研究科(研究院), 助教 (00753906)
• Co-Investigator(Renkei-kenkyūsha): KITAHARA Ryou 立命館大学, 薬学部, 教授 (70512284)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 医薬分子設計 / 分子標的薬 / がん / シグナル伝達

Outline of Final Research Achievements

ras proto-oncogene products Ras, is a member of small GTPases, which is frequently activated in a wide variety of human cancers, making them promising anti-cancer drug targets. In the present study, we determined the novel druggable pocket structure of Ras by Synchrotron X-ray crystallography utilizing Humid Air and Glue-coating (HAG) mounting method, which unveiled the molecular basis of conformational transition between the open and closed pocket structures. Molecular Dynamics simulation of the solved structures lead us to a reasonable agreement with experimental observations and the consequent scenarios on the transition. Further, crystal structure analysis of Ras/fragment-compound complex by cross-linking method gave us useful information on the structure-based design of Ras inhibitors.

Free Research Field

創薬科学