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==Structure of HsICDH1:Mg(II):ICT:NADPH(50%) complex reveals structural basis for observation of half-sites reactivity==
<StructureSection load='6pay' size='340' side='right'caption='[[6pay]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6pay]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PAY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PAY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.199&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=ICT:ISOCITRIC+ACID'>ICT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6pay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pay OCA], [https://pdbe.org/6pay PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pay RCSB], [https://www.ebi.ac.uk/pdbsum/6pay PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pay ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[https://omim.org/entry/137800 137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
== Function ==
[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human isocitrate dehydrogenase 1 (HsICDH1) is a cytoplasmic homodimeric Mg(II)-dependent enzyme that converts d-isocitrate (D-ICT) and NADP(+) to alpha-ketoglutarate (AKG), CO2, and NADPH. The active sites are formed at the subunit interface and incorporate residues from both protomers. The turnover number titrates hyperbolically from 17.5 s(-1) to a minimum of 7 s(-1) with an increasing enzyme concentration. As isolated, the enzyme adopts an inactive open conformation and binds NADPH tightly. The open conformation displaces three of the eight residues that bind D-ICT and Mg(II). Enzyme activation occurs with the addition of Mg(II) or D-ICT with a rate constant of 0.12 s(-1). The addition of both Mg(II) and D-ICT activates the enzyme with a rate constant of 0.6 s(-1) and displaces half of the bound NADPH. This indicates that HsICDH1 may have a half-site mechanism in which the active sites alternate in catalysis. The X-ray crystal structure of the half-site activated complex reveals asymmetry in the homodimer with a single NADPH bound. The structure also indicates a pseudotetramer interface that impedes the egress of NADPH consistent with the suppression of the turnover number at high enzyme concentrations. When the half-site activated form of the enzyme is reacted with NADP(+), NADPH forms with a rate constant of 204 s(-1) followed by a shift in the NADPH absorption spectrum with a rate constant of 28 s(-1). These data indicate the accumulation of two intermediate states. Once D-ICT is exhausted, HsICDH1 relaxes to the inactive open state with a rate constant of approximately 3 s(-1).

Transient-State Analysis of Human Isocitrate Dehydrogenase I: Accounting for the Interconversion of Active and Non-Active Conformational States.,Roman JV, Melkonian TR, Silvaggi NR, Moran GR Biochemistry. 2019 Dec 31;58(52):5366-5380. doi: 10.1021/acs.biochem.9b00518., Epub 2019 Sep 10. PMID:31478653<ref>PMID:31478653</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6pay" style="background-color:#fffaf0;"></div>

==See Also==
*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Melkonian TR]]
[[Category: Moran GR]]
[[Category: Roman JV]]
[[Category: Silvaggi NR]]