5lge

From Proteopedia

(Difference between revisions)

Revision as of 10:36, 12 August 2020

Crystal Structure of human IDH1 mutant (R132H) in complex with NADP+ and an Inhibitor related to BAY 1436032

Structural highlights

5lge is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
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

Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo.,Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D, Capper D, Sahm F, Eisel J, Beck AC, Jugold M, Eichwald V, Kaulfuss S, Panknin O, Rehwinkel H, Zimmermann K, Hillig RC, Guenther J, Toschi L, Neuhaus R, Haegebart A, Hess-Stumpp H, Bauser M, Wick W, Unterberg A, Herold-Mende C, Platten M, von Deimling A Acta Neuropathol. 2017 Jan 25. doi: 10.1007/s00401-017-1677-y. PMID:28124097^[1]

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

References

↑ Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D, Capper D, Sahm F, Eisel J, Beck AC, Jugold M, Eichwald V, Kaulfuss S, Panknin O, Rehwinkel H, Zimmermann K, Hillig RC, Guenther J, Toschi L, Neuhaus R, Haegebart A, Hess-Stumpp H, Bauser M, Wick W, Unterberg A, Herold-Mende C, Platten M, von Deimling A. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol. 2017 Jan 25. doi: 10.1007/s00401-017-1677-y. PMID:28124097 doi:http://dx.doi.org/10.1007/s00401-017-1677-y

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/5lge"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of human IDH1 mutant (R132H) in complex with NADP+ and an Inhibitor related to BAY 1436032==
-<StructureSection load='5lge' size='340' side='right' caption='[[5lge]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='5lge' size='340' side='right'caption='[[5lge]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5lge]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LGE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LGE FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5lge]] is a 4 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=5LGE OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5LGE FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VN:2-[(4-PROPAN-2-YLPHENYL)AMINO]-1-[(1~{S},5~{S})-3,3,5-TRIMETHYLCYCLOHEXYL]BENZIMIDAZOLE-5-CARBOXYLIC+ACID'>6VN</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6VN:2-[(4-PROPAN-2-YLPHENYL)AMINO]-1-[(1~{S},5~{S})-3,3,5-TRIMETHYLCYCLOHEXYL]BENZIMIDAZOLE-5-CARBOXYLIC+ACID'>6VN</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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 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=5lge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lge OCA], [http://pdbe.org/5lge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lge RCSB], [http://www.ebi.ac.uk/pdbsum/5lge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lge 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=5lge FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lge OCA], [http://pdbe.org/5lge PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lge RCSB], [http://www.ebi.ac.uk/pdbsum/5lge PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lge ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 5lge" 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: Hars, U]]
 [[Category: Hillig, R C]]

5lge

From Proteopedia

Revision as of 10:36, 12 August 2020

Crystal Structure of human IDH1 mutant (R132H) in complex with NADP+ and an Inhibitor related to BAY 1436032

Structural highlights

Disease

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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