8hb9

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of Human IDH1 R132H Mutant in Complex with NADPH and Compound IHMT-IDH1-053

Structural highlights

8hb9 is a 4 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 2.8Å
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

Through a structure-based irreversible drug design approach, we have discovered a highly potent IDH1-mutant inhibitor compound 16 (IHMT-IDH1-053) (IC(50) = 4.7 nM), which displays high selectivity against IDH1 mutants over IDH1 wt and IDH2 wt/mutants. The crystal structure demonstrates that 16 binds to the IDH1 R132H protein in the allosteric pocket adjacent to the NAPDH binding pocket through a covalent bond with residue Cys269. 16 inhibits 2-hydroxyglutarate (2-HG) production in IDH1 R132H mutant transfected 293T cells (IC(50) = 28 nM). In addition, it inhibits the proliferation of HT1080 cell line and primary AML cells which both bear IDH1 R132 mutants. In vivo, 16 inhibits 2-HG level in a HT1080 xenograft mouse model. Our study suggested that 16 would be a new pharmacological tool to study IDH1 mutant-related pathology and the covalent binding mode provided a novel approach for designing irreversible IDH1 inhibitors.

Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.,Liang Q, Wang B, Zou F, Guo G, Wang W, Wang W, Liu Q, Shen L, Hu C, Wang W, Wang A, Huang T, He Y, Xia R, Ge J, Liu J, Liu Q Eur J Med Chem. 2023 Aug 5;256:115411. doi: 10.1016/j.ejmech.2023.115411. Epub , 2023 May 12. PMID:37209613^[1]

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

References

↑ Liang Q, Wang B, Zou F, Guo G, Wang W, Wang W, Liu Q, Shen L, Hu C, Wang W, Wang A, Huang T, He Y, Xia R, Ge J, Liu J, Liu Q. Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor. Eur J Med Chem. 2023 Aug 5;256:115411. PMID:37209613 doi:10.1016/j.ejmech.2023.115411

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/8hb9"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8hb9]] is a 4 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=8HB9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HB9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=R1R:[2-[2-[[1-[4-[(1S)-1-[[5-fluoranyl-4-[(4S)-2-oxidanylidene-4-propan-2-yl-1,3-oxazolidin-3-yl]pyrimidin-2-yl]amino]ethyl]phenyl]piperidin-4-yl]sulfamoyl]ethylsulfanylmethyl]-3-oxidanylidene-propyl]-trimethyl-azanium'>R1R</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]] 2.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=R1R:[2-[2-[[1-[4-[(1~{S})-1-[[5-fluoranyl-4-[(4~{S})-2-oxidanylidene-4-propan-2-yl-1,3-oxazolidin-3-yl]pyrimidin-2-yl]amino]ethyl]phenyl]piperidin-4-yl]sulfamoyl]ethylsulfanylmethyl]-3-oxidanylidene-propyl]-trimethyl-azanium'>R1R</scene></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=8hb9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hb9 OCA], [https://pdbe.org/8hb9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hb9 RCSB], [https://www.ebi.ac.uk/pdbsum/8hb9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hb9 ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Through a structure-based irreversible drug design approach, we have discovered a highly potent IDH1-mutant inhibitor compound 16 (IHMT-IDH1-053) (IC(50) = 4.7 nM), which displays high selectivity against IDH1 mutants over IDH1 wt and IDH2 wt/mutants. The crystal structure demonstrates that 16 binds to the IDH1 R132H protein in the allosteric pocket adjacent to the NAPDH binding pocket through a covalent bond with residue Cys269. 16 inhibits 2-hydroxyglutarate (2-HG) production in IDH1 R132H mutant transfected 293T cells (IC(50) = 28 nM). In addition, it inhibits the proliferation of HT1080 cell line and primary AML cells which both bear IDH1 R132 mutants. In vivo, 16 inhibits 2-HG level in a HT1080 xenograft mouse model. Our study suggested that 16 would be a new pharmacological tool to study IDH1 mutant-related pathology and the covalent binding mode provided a novel approach for designing irreversible IDH1 inhibitors.
+Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.,Liang Q, Wang B, Zou F, Guo G, Wang W, Wang W, Liu Q, Shen L, Hu C, Wang W, Wang A, Huang T, He Y, Xia R, Ge J, Liu J, Liu Q Eur J Med Chem. 2023 Aug 5;256:115411. doi: 10.1016/j.ejmech.2023.115411. Epub , 2023 May 12. PMID:37209613<ref>PMID:37209613</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 8hb9" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>

8hb9

From Proteopedia

Current revision

Crystal Structure of Human IDH1 R132H Mutant in Complex with NADPH and Compound IHMT-IDH1-053

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox