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.

Summary for 6L59

• Entry DOI: 10.2210/pdb6l59/pdb
• Descriptor: Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial, Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: tca cycle, nad-isocitrate dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 77355.44

Authors

Sun, P.,Ding, J. (deposition date: 2019-10-22, release date: 2020-04-29, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.254 Å)