Study on the reaction mechanism of type II NADH dehydrogenase by structural and biochemical analyses of the enzyme-inhibitor interaction.

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K07005
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kagawa University
• Principal Investigator: Yamashita Tetsuo 香川大学, 医学部, 助教 (80444727)
• Co-Investigator(Renkei-kenkyūsha): KITA Kiyoshi 長崎大学, 熱帯医学・グローバルヘルス研究科, 教授 (90134444) ; HARADA Shigeharu 京都工芸繊維大学, 工芸科学研究科, 教授 (80156504) ; SHIBA Tomoo 京都工芸繊維大学, 工芸科学研究科, 准教授 (80401206) ; Inaoka Daniel K 長崎大学, 熱帯医学・グローバルヘルス研究科, 助教 (10623803)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: NADH dehydrogenase / ユビキノン結合部位 / X線結晶構造解析 / 共結晶 / 阻害剤

Outline of Final Research Achievements

Type II NADH dehydrogenase (NDH-2) has emerged as a potential therapeutic target for drugs targeting human pathogenic bacteria and parasites, because mammals have only proton-pumping NADH dehydrogenase (complex I) but not NDH-2. In order to develop highly selective effectiveness inhibitors, it is necessary to understand the reaction mechanism of NDH-2 and its structural basis and investigate the interaction between protein and inhibitor at the level of a molecule. Furthermore, the binding sites of the substrates, NADH and ubiquinone, have to be identified. A crystal structure of yeast NDH-2 (Ndi1) in complex with ubiquinone has already been revealed, but there has been controversy regarding the physiological ubiquinone binding site. In the present study, the inherent ubiquinone-binding site of yeast Ndi1 was identified by structures binding novel competitive- and mixed-type inhibitors, and biochemical analysis.

Free Research Field

生化学