Molecular mechanism of the dual regulatory roles of ATP on the αγ heterodimer of human NAD-dependent isocitrate dehydrogenase.

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 α₂βγ 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 (α^Mgγ^Mg+CIT+ATP) and to both the allosteric site and the active site (α^Mg+ATPγ^Mg+CIT+ATP). Structural data show that ATP at low concentrations can mimic ADP to bind to the allosteric

SUBMITTER: Sun P 

PROVIDER: S-EPMC7148312 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature