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| | <StructureSection load='6tgw' size='340' side='right'caption='[[6tgw]], [[Resolution|resolution]] 2.80Å' scene=''> | | <StructureSection load='6tgw' size='340' side='right'caption='[[6tgw]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tgw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TGW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TGW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tgw]] 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=6TGW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TGW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N98:methyl+5-(1,3-benzodioxol-5-yl)-2-phenyl-pyrazolo[1,5-a]pyrimidine-7-carboxylate'>N98</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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]] 2.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[5fhz|5fhz]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N98:methyl+5-(1,3-benzodioxol-5-yl)-2-phenyl-pyrazolo[1,5-a]pyrimidine-7-carboxylate'>N98</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ALDH1A3, ALDH6 ([https://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'>[https://en.wikipedia.org/wiki/Retinal_dehydrogenase Retinal dehydrogenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.1.36 1.2.1.36] </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=6tgw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tgw OCA], [https://pdbe.org/6tgw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tgw RCSB], [https://www.ebi.ac.uk/pdbsum/6tgw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tgw ProSAT]</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=6tgw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tgw OCA], [https://pdbe.org/6tgw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tgw RCSB], [https://www.ebi.ac.uk/pdbsum/6tgw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tgw ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/AL1A3_HUMAN AL1A3_HUMAN]] Isolated anophthalmia - microphthalmia. The disease is caused by mutations affecting the gene represented in this entry.
| + | [https://www.uniprot.org/uniprot/AL1A3_HUMAN AL1A3_HUMAN] Isolated anophthalmia - microphthalmia. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/AL1A3_HUMAN AL1A3_HUMAN]] Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Seems to be the key enzyme in the formation of an RA gradient along the dorso-ventral axis during the early eye development and also in the development of the olfactory system (By similarity).
| + | [https://www.uniprot.org/uniprot/AL1A3_HUMAN AL1A3_HUMAN] Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Seems to be the key enzyme in the formation of an RA gradient along the dorso-ventral axis during the early eye development and also in the development of the olfactory system (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Retinal dehydrogenase]]
| + | [[Category: Garavaglia S]] |
| - | [[Category: Garavaglia, S]] | + | [[Category: Rizzi M]] |
| - | [[Category: Rizzi, M]] | + | |
| - | [[Category: Aldehyde dehydrogenase aldh inhibitor cancer stem cell]]
| + | |
| - | [[Category: Aldh1a3]]
| + | |
| - | [[Category: Glioblastoma mesenchymal stem cell stem cell]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Disease
AL1A3_HUMAN Isolated anophthalmia - microphthalmia. The disease is caused by mutations affecting the gene represented in this entry.
Function
AL1A3_HUMAN Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Seems to be the key enzyme in the formation of an RA gradient along the dorso-ventral axis during the early eye development and also in the development of the olfactory system (By similarity).
Publication Abstract from PubMed
Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs may regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent, and selective inhibitors of key ALDH enzymes may represent a novel CSC-directed treatment paradigm for ALDH(+) cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, our structure of human ALDH1A3 combined with in silico modeling identifies a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis reveals that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation.
A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells.,Li J, Garavaglia S, Ye Z, Moretti A, Belyaeva OV, Beiser A, Ibrahim M, Wilk A, McClellan S, Klyuyeva AV, Goggans KR, Kedishvili NY, Salter EA, Wierzbicki A, Migaud ME, Mullett SJ, Yates NA, Camacho CJ, Rizzi M, Sobol RW Commun Biol. 2021 Dec 21;4(1):1420. doi: 10.1038/s42003-021-02949-7. PMID:34934174[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Li J, Garavaglia S, Ye Z, Moretti A, Belyaeva OV, Beiser A, Ibrahim M, Wilk A, McClellan S, Klyuyeva AV, Goggans KR, Kedishvili NY, Salter EA, Wierzbicki A, Migaud ME, Mullett SJ, Yates NA, Camacho CJ, Rizzi M, Sobol RW. A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells. Commun Biol. 2021 Dec 21;4(1):1420. doi: 10.1038/s42003-021-02949-7. PMID:34934174 doi:http://dx.doi.org/10.1038/s42003-021-02949-7
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