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5sun

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Revision as of 11:11, 16 September 2020

IDH1 R132H in complex with IDH146

Structural highlights

5sun 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:	5svn, 5svo, 5svf
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

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity.,Xie X, Baird D, Bowen K, Capka V, Chen J, Chenail G, Cho Y, Dooley J, Farsidjani A, Fortin P, Kohls D, Kulathila R, Lin F, McKay D, Rodrigues L, Sage D, Toure BB, van der Plas S, Wright K, Xu M, Yin H, Levell J, Pagliarini RA Structure. 2017 Mar 7;25(3):506-513. doi: 10.1016/j.str.2016.12.017. Epub 2017, Jan 26. PMID:28132785^[1]

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

References

↑ Xie X, Baird D, Bowen K, Capka V, Chen J, Chenail G, Cho Y, Dooley J, Farsidjani A, Fortin P, Kohls D, Kulathila R, Lin F, McKay D, Rodrigues L, Sage D, Toure BB, van der Plas S, Wright K, Xu M, Yin H, Levell J, Pagliarini RA. Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity. Structure. 2017 Mar 7;25(3):506-513. doi: 10.1016/j.str.2016.12.017. Epub 2017, Jan 26. PMID:28132785 doi:http://dx.doi.org/10.1016/j.str.2016.12.017

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/5sun"

@@ Line 1: / Line 1: @@
 ==IDH1 R132H in complex with IDH146==
-<StructureSection load='5sun' size='340' side='right' caption='[[5sun]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
+<StructureSection load='5sun' size='340' side='right'caption='[[5sun]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5sun]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SUN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5SUN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5sun]] 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=5SUN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5SUN FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=70Q:3-BENZYL-N-[3-(DIMETHYLSULFAMOYL)PHENYL]-4-OXO-3,4-DIHYDROPHTHALAZINE-1-CARBOXAMIDE'>70Q</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=70Q:3-BENZYL-N-[3-(DIMETHYLSULFAMOYL)PHENYL]-4-OXO-3,4-DIHYDROPHTHALAZINE-1-CARBOXAMIDE'>70Q</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5svn|5svn]], [[5svo|5svo]], [[5svf|5svf]]</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=5sun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sun OCA], [http://pdbe.org/5sun PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5sun RCSB], [http://www.ebi.ac.uk/pdbsum/5sun PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5sun ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5sun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sun OCA], [http://pdbe.org/5sun PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5sun RCSB], [http://www.ebi.ac.uk/pdbsum/5sun PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5sun ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5sun" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Kulathila, R]]
 [[Category: Xie, X]]

5sun

From Proteopedia

Revision as of 11:11, 16 September 2020

IDH1 R132H in complex with IDH146

Structural highlights

Disease

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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