Strucutral physiology of P-type ATPases

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02426
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Nagoya University
• Principal Investigator: ABE Kazuhiro 名古屋大学, 細胞生理学研究センター, 准教授 (60596188)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: P-type ATPase / membrane protein / Cryo-EM / gastric proton pump / Flippase / biochemistry / structgural biology

Outline of Final Research Achievements

We determined binding mode of several inhibitors/drugs (Tanaka et al., 2021, J Med Chem). Using these drug-bound structures as template, we developed De novo inhibitors employing AI-driven pratform (Abe et al., 2022, Commun Biol).
To clarify the specificity of cation transport among closely-related isoforms, we generate a mutant proton pump in which two K+ is bound (Abe et al., 2021, Nat Cmooun) and a mutant that behave like sodium pump (Young et al., 2022, Nat Commun).
We also determined cryo-EM structure of a soium pump isoform expressed in brine shrimp living in dead sea (Artigas et al., 2023, PNAS)

Free Research Field

生化学　構造生物学

Academic Significance and Societal Importance of the Research Achievements

構造とAIを駆使したドラッグデザインの枠組みは、胃プロトンポンプだけでなく、薬剤結合構造既知のタンパク質一般に広く応用が期待される。
プロトンポンプの輸送イオンを変換することに成功したことによって、近縁のカチオンポンプの作動機構の理解に大きく貢献した。