6KDE

Crystal structure of the alpha beta heterodimer of human IDH3 in complex with Ca(2+)

Summary for 6KDE

• Entry DOI: 10.2210/pdb6kde/pdb
• Descriptor: Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial, Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial, CALCIUM ION (3 entities in total)
• Functional Keywords: nad dependent isocitrate dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 153140.09

Authors

Sun, P.,Ding, J. (deposition date: 2019-07-02, release date: 2019-09-25, Last modification date: 2023-11-22)

Primary citation

Sun, P.,Ma, T.,Zhang, T.,Zhu, H.,Zhang, J.,Liu, Y.,Ding, J.
Molecular basis for the function of the alpha beta heterodimer of human NAD-dependent isocitrate dehydrogenase.
J.Biol.Chem., 294:16214-16227, 2019

PubMed Abstract: Mammalian mitochondrial NAD-dependent isocitrate dehydrogenase (NAD-IDH) catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the tricarboxylic acid cycle. It exists as the αβγ heterotetramer composed of the αβ and αγ heterodimers. Different from the αγ heterodimer that can be allosterically activated by CIT and ADP, the αβ heterodimer cannot be allosterically regulated by the activators; however, the molecular mechanism is unclear. We report here the crystal structures of the αβ heterodimer of human NAD-IDH with the α subunit in apo form and in Ca-bound, NAD-bound, and NADH-bound forms. Structural analyses and comparisons reveal that the αβ heterodimer has a similar yet more compact overall structure compared with the αγ heterodimer and contains a pseudo-allosteric site that is structurally different from the allosteric site. In particular, the β3-α3 and β12-α8 loops of the β subunit at the pseudo-allosteric site adopt significantly different conformations from those of the γ subunit at the allosteric site and hence impede the binding of the activators, explaining why the αβ heterodimer cannot be allosterically regulated by the activators. The structural data also show that NADH can compete with NAD to bind to the active site and inhibits the activity of the αβ heterodimer. These findings together with the biochemical data reveal the molecular basis for the function of the αβ heterodimer of human NAD-IDH.

PubMed: 31515270
DOI: 10.1074/jbc.RA119.010099

Experimental method

X-RAY DIFFRACTION (2.999 Å)