View source for 1t0l


==Crystal structure of human cytosolic NADP(+)-dependent isocitrate dehydrogenase in complex with NADP, isocitrate, and calcium(2+)==
<StructureSection load='1t0l' size='340' side='right'caption='[[1t0l]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1t0l]] 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=1T0L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1T0L 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]] 2.41&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ICT:ISOCITRIC+ACID'>ICT</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=1t0l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t0l OCA], [https://pdbe.org/1t0l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1t0l RCSB], [https://www.ebi.ac.uk/pdbsum/1t0l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1t0l 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] 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/t0/1t0l_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1t0l ConSurf].
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== Publication Abstract from PubMed ==
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, and regulation of the enzymatic activity of IDHs is crucial for their biological functions. Bacterial IDHs are reversibly regulated by phosphorylation of a strictly conserved serine residue at the active site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse important biological functions; however, their regulatory mechanism remains unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically relevant conformational states of the enzyme that differ substantially in the structure of the active site and in the overall structure. A structural segment at the active site that forms a conserved alpha-helix in all known NADP-IDH structures assumes a loop conformation in the open, inactive form of HcIDH; a partially unraveled alpha-helix in the semi-open, intermediate form; and an alpha-helix in the closed, active form. The side chain of Asp279 of this segment occupies the isocitrate-binding site and forms hydrogen bonds with Ser94 (the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the metal ion in the active form. The structural data led us to propose a novel self-regulatory mechanism for HcIDH that mimics the phosphorylation mechanism used by the bacterial homologs, consistent with biochemical and biological data. This mechanism might be applicable to other eukaryotic NADP-IDHs. The results also provide insights into the recognition and specificity of substrate and cofactor by eukaryotic NADP-IDHs.

Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity.,Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J J Biol Chem. 2004 Aug 6;279(32):33946-57. Epub 2004 Jun 1. PMID:15173171<ref>PMID:15173171</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arnold E]]
[[Category: Ding J]]
[[Category: Huang Q]]
[[Category: Peng B]]
[[Category: Xu X]]
[[Category: Zhao J]]