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5k11

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Revision as of 08:47, 18 July 2018

Cryo-EM structure of isocitrate dehydrogenase (IDH1) in inhibitor-bound state

Structural highlights

5k11 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	5k0z, 5k10, 5k12
Gene:	IDH1, PICD (HUMAN)
Activity:	Isocitrate dehydrogenase (NADP(+)), with EC number 1.1.1.42
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM: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.

Publication Abstract from PubMed

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 >/= 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 < 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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Merk A, Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis MI, Pragani R, Boxer MB, Earl LA, Milne JL, Subramaniam S. Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery. Cell. 2016 Jun 16;165(7):1698-707. doi: 10.1016/j.cell.2016.05.040. Epub 2016 May, 26. PMID:27238019 doi:http://dx.doi.org/10.1016/j.cell.2016.05.040

1 Structural highlights
2 Disease
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5k11"

@@ Line 3: / Line 3: @@
 <StructureSection load='5k11' size='340' side='right' caption='[[5k11]], [[Resolution|resolution]] 3.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5k11]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K11 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K11 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5k11]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K11 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K11 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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k0z|5k0z]], [[5k10|5k10]], [[5k12|5k12]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDH1, PICD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5k11 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k11 OCA], [http://pdbe.org/5k11 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k11 RCSB], [http://www.ebi.ac.uk/pdbsum/5k11 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k11 ProSAT]</span></td></tr>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5k11" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Isocitrate dehydrogenase|Isocitrate dehydrogenase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Banerjee, S]]
 [[Category: Bartesaghi, A]]

5k11

From Proteopedia

Revision as of 08:47, 18 July 2018

Cryo-EM structure of isocitrate dehydrogenase (IDH1) in inhibitor-bound state

Structural highlights

Disease

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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