6L59

Crystal structure of the alpha gamma heterodimer of human IDH3 in complex with CIT, Mg and ATP binding at allosteric site and Mg, ATP binding at active site.

6L59 の概要

• エントリーDOI: 10.2210/pdb6l59/pdb
• 分子名称: Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial, Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: tca cycle, nad-isocitrate dehydrogenase, oxidoreductase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77355.44

構造登録者

Sun, P.,Ding, J. (登録日: 2019-10-22, 公開日: 2020-04-29, 最終更新日: 2023-11-22)

主引用文献

Sun, P.,Bai, T.,Ma, T.,Ding, J.
Molecular mechanism of the dual regulatory roles of ATP on the alpha gamma heterodimer of human NAD-dependent isocitrate dehydrogenase.
Sci Rep, 10:6225-6225, 2020

PubMed Abstract: Human NAD-dependent isocitrate dehydrogenase (NAD-IDH) is responsible for the catalytic conversion of isocitrate into α-ketoglutarate in the Krebs cycle. This enzyme exists as the αβγ heterotetramer composed of the αβ and αγ heterodimers. Our previous biochemical data showed that the αγ heterodimer and the holoenzyme can be activated by low concentrations of ATP but inhibited by high concentrations of ATP; however, the molecular mechanism was unknown. Here, we report the crystal structures of the αγ heterodimer with ATP binding only to the allosteric site (αγ) and to both the allosteric site and the active site (αγ). Structural data show that ATP at low concentrations can mimic ADP to bind to the allosteric site, which stabilizes CIT binding and leads the enzyme to adopt an active conformation, revealing why the enzyme can be activated by low concentrations of ATP. On the other hand, at high concentrations ATP is competitive with NAD for binding to the catalytic site. In addition, our biochemical data show that high concentrations of ATP promote the formation of metal ion-ATP chelates. This reduces the concentration of free metal ion available for the catalytic reaction, and thus further inhibits the enzymatic activity. The combination of these two effects accounts for the inhibition of the enzyme at high concentrations of ATP. Taken together, our structural and biochemical data reveal the molecular mechanism for the dual regulatory roles of ATP on the αγ heterodimer of human NAD-IDH.

PubMed: 32277159
DOI: 10.1038/s41598-020-63425-6

実験手法

X-RAY DIFFRACTION (2.254 Å)