|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6q6f' size='340' side='right'caption='[[6q6f]], [[Resolution|resolution]] 3.30Å' scene=''> | | <StructureSection load='6q6f' size='340' side='right'caption='[[6q6f]], [[Resolution|resolution]] 3.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6q6f]] 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=6Q6F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q6F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6q6f]] is a 2 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=6Q6F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q6F FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HJQ:(2~{R})-2-[2-[(3~{R})-3-(4-fluorophenyl)pyrrolidin-1-yl]ethyl]-1,4-dimethyl-piperazine'>HJQ</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]] 3.3Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HJQ:(2~{R})-2-[2-[(3~{R})-3-(4-fluorophenyl)pyrrolidin-1-yl]ethyl]-1,4-dimethyl-piperazine'>HJQ</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6q6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q6f OCA], [https://pdbe.org/6q6f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q6f RCSB], [https://www.ebi.ac.uk/pdbsum/6q6f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q6f ProSAT]</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=6q6f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q6f OCA], [http://pdbe.org/6q6f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q6f RCSB], [http://www.ebi.ac.uk/pdbsum/6q6f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q6f ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 21: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6q6f" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6q6f" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chaturvedi, A]] | + | [[Category: Araujo Cruz MM]] |
| - | [[Category: Cruz, M M.Araujo]] | + | [[Category: Chaturvedi A]] |
| - | [[Category: Ganser, A]] | + | [[Category: Ganser A]] |
| - | [[Category: Goerlich, K]] | + | [[Category: Goerlich K]] |
| - | [[Category: Goparaju, R]] | + | [[Category: Goparaju R]] |
| - | [[Category: Gupta, C]] | + | [[Category: Gupta C]] |
| - | [[Category: Heuser, M]] | + | [[Category: Heuser M]] |
| - | [[Category: Kloos, A]] | + | [[Category: Kloos A]] |
| - | [[Category: Kluenemann, T]] | + | [[Category: Kluenemann T]] |
| - | [[Category: Preller, M]] | + | [[Category: Preller M]] |
| - | [[Category: Schottmann, R]] | + | [[Category: Schottmann R]] |
| - | [[Category: Struys, E A]] | + | [[Category: Struys EA]] |
| - | [[Category: Cytoplasmic]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Isocitrate dehydrogenase]]
| + | |
| - | [[Category: Mutant r132h]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
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
Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone- and DNA-hypermethylation through the inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding, and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with HMS-101 showed a marked upregulation of the differentiation-associated transcription factors CEBPA and PU.1, and a decrease in cell cycle regulator cyclin A2. In addition, the compound attenuated histone hypermethylation. Together, HMS-101 is a unique inhibitor that binds to the active site of IDH1mut directly and is active in IDH1mut preclinical models.
In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site.,Chaturvedi A, Goparaju R, Gupta C, Weder J, Klunemann T, Araujo Cruz MM, Kloos A, Goerlich K, Schottmann R, Othman B, Struys EA, Bahre H, Grote-Koska D, Brand K, Ganser A, Preller M, Heuser M Leukemia. 2019 Oct 4. pii: 10.1038/s41375-019-0582-x. doi:, 10.1038/s41375-019-0582-x. PMID:31586149[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chaturvedi A, Goparaju R, Gupta C, Weder J, Klunemann T, Araujo Cruz MM, Kloos A, Goerlich K, Schottmann R, Othman B, Struys EA, Bahre H, Grote-Koska D, Brand K, Ganser A, Preller M, Heuser M. In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site. Leukemia. 2019 Oct 4. pii: 10.1038/s41375-019-0582-x. doi:, 10.1038/s41375-019-0582-x. PMID:31586149 doi:http://dx.doi.org/10.1038/s41375-019-0582-x
|
