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4kzo

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Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate

Structural highlights

4kzo is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.204Å
Ligands:	, , ,
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.

Function

IDHC_HUMAN

Publication Abstract from PubMed

The human, cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) reversibly converts isocitrate to alpha-ketoglutarate (alphaKG). Cancer-associated somatic mutations in IDH1 result in a loss of this normal function but a gain in a new or neomorphic ability to convert alphaKG to the oncometabolite 2-hydroxyglutarate (2HG). To improve our understanding of the basis for this phenomenon, we have conducted a detailed kinetic study of wild-type IDH1 as well as the known 2HG-producing clinical R132H and G97D mutants and mechanistic Y139D and (newly described) G97N mutants. In the reductive direction of the normal reaction (alphaKG to isocitrate), dead-end inhibition studies suggest that wild-type IDH1 goes through a random sequential mechanism, similar to previous reports on related mammalian IDH enzymes. However, analogous experiments studying the reductive neomorphic reaction (alphaKG to 2HG) with the mutant forms of IDH1 are more consistent with an ordered sequential mechanism, with NADPH binding before alphaKG. This result was further confirmed by primary kinetic isotope effects for which saturating with alphaKG greatly reduced the observed isotope effect on (D)(V/K)NADPH. For the mutant IDH1 enzyme, the change in mechanism was consistently associated with reduced efficiencies in the use of alphaKG as a substrate and enhanced efficiencies using NADPH as a substrate. We propose that the sum of these kinetic changes allows the mutant IDH1 enzymes to reductively trap alphaKG directly into 2HG, rather than allowing it to react with carbon dioxide and form isocitrate, as occurs in the wild-type enzyme.

Mutant IDH1 Enhances the Production of 2-Hydroxyglutarate Due to Its Kinetic Mechanism.,Rendina AR, Pietrak B, Smallwood A, Zhao H, Qi H, Quinn C, Adams ND, Concha N, Duraiswami C, Thrall SH, Sweitzer S, Schwartz B Biochemistry. 2013 Jul 2;52(26):4563-77. doi: 10.1021/bi400514k. Epub 2013 Jun, 21. PMID:23731180^[1]

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

References

↑ Rendina AR, Pietrak B, Smallwood A, Zhao H, Qi H, Quinn C, Adams ND, Concha N, Duraiswami C, Thrall SH, Sweitzer S, Schwartz B. Mutant IDH1 Enhances the Production of 2-Hydroxyglutarate Due to Its Kinetic Mechanism. Biochemistry. 2013 Jul 2;52(26):4563-77. doi: 10.1021/bi400514k. Epub 2013 Jun, 21. PMID:23731180 doi:10.1021/bi400514k

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4kzo"

Categories: Homo sapiens | Large Structures | Concha NO | Smallwood AM

@@ Line 1: / Line 1: @@
 ==Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate==
-<StructureSection load='4kzo' size='340' side='right' caption='[[4kzo]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+<StructureSection load='4kzo' size='340' side='right'caption='[[4kzo]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4kzo]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KZO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KZO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4kzo]] is a 3 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=4KZO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KZO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.204&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4l03|4l03]], [[4l04|4l04]], [[4l06|4l06]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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 Homo sapiens])</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=4kzo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kzo OCA], [https://pdbe.org/4kzo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kzo RCSB], [https://www.ebi.ac.uk/pdbsum/4kzo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kzo ProSAT]</span></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=4kzo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kzo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kzo RCSB], [http://www.ebi.ac.uk/pdbsum/4kzo PDBsum]</span></td></tr>
 </table>
 == 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.
+== Function ==
+[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4kzo" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Isocitrate dehydrogenase|Isocitrate dehydrogenase]]
+*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
 == References ==
 <references/>
@@ Line 27: / Line 29: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Concha, N O]]
+[[Category: Large Structures]]
-[[Category: Smallwood, A M]]
+[[Category: Concha NO]]
-[[Category: Cytosolic]]
+[[Category: Smallwood AM]]
-[[Category: Oxidoreductase]]

4kzo

From Proteopedia

Current revision

Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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