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==Cryo-EM structure of isocitrate dehydrogenase (IDH1)==
==Cryo-EM structure of isocitrate dehydrogenase (IDH1)==
<StructureSection load='5k10' size='340' side='right' caption='[[5k10]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
<SX load='5k10' size='340' side='right' viewer='molstar' caption='[[5k10]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5k10]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K10 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K10 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5k10]] is a 2 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=5K10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K10 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.8&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k0z|5k0z]], [[5k11|5k11]], [[5k12|5k12]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </span></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=5k10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k10 OCA], [https://pdbe.org/5k10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k10 RCSB], [https://www.ebi.ac.uk/pdbsum/5k10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k10 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5k10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k10 OCA], [http://pdbe.org/5k10 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k10 RCSB], [http://www.ebi.ac.uk/pdbsum/5k10 PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[http://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.  
[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.
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]
Recent advances in single-particle cryoelecton microscopy (cryo-EM) are enabling generation of numerous near-atomic resolution structures for well-ordered protein complexes with sizes &gt;/= approximately 200 kDa. Whether cryo-EM methods are equally useful for high-resolution structural analysis of smaller, dynamic protein complexes such as those involved in cellular metabolism remains an important question. Here, we present 3.8 A resolution cryo-EM structures of the cancer target isocitrate dehydrogenase (93 kDa) and identify the nature of conformational changes induced by binding of the allosteric small-molecule inhibitor ML309. We also report 2.8-A- and 1.8-A-resolution structures of lactate dehydrogenase (145 kDa) and glutamate dehydrogenase (334 kDa), respectively. With these results, two perceived barriers in single-particle cryo-EM are overcome: (1) crossing 2 A resolution and (2) obtaining structures of proteins with sizes &lt; 100 kDa, demonstrating that cryo-EM can be used to investigate a broad spectrum of drug-target interactions and dynamic conformational states.


Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery.,Merk A, Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis MI, Pragani R, Boxer MB, Earl LA, Milne JL, Subramaniam S Cell. 2016 Jun 16;165(7):1698-707. doi: 10.1016/j.cell.2016.05.040. Epub 2016 May, 26. PMID:27238019<ref>PMID:27238019</ref>
==See Also==
 
*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5k10" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</SX>
[[Category: Banerjee, S]]
[[Category: Homo sapiens]]
[[Category: Bartesaghi, A]]
[[Category: Large Structures]]
[[Category: Earl, L]]
[[Category: Banerjee S]]
[[Category: Falconieri, V]]
[[Category: Bartesaghi A]]
[[Category: Merk, A]]
[[Category: Earl L]]
[[Category: Milne, J]]
[[Category: Falconieri V]]
[[Category: Rao, P]]
[[Category: Merk A]]
[[Category: Subramaniam, S]]
[[Category: Milne J]]
[[Category: Isocitrate dehydrogenase]]
[[Category: Rao P]]
[[Category: Oxidoreductase]]
[[Category: Subramaniam S]]
[[Category: Small metabolic complex]]

Latest revision as of 15:38, 6 March 2024

Cryo-EM structure of isocitrate dehydrogenase (IDH1)Cryo-EM structure of isocitrate dehydrogenase (IDH1)

5k10, resolution 3.80Å

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