7a6q: Difference between revisions

Latest revision as of 06:29, 1 October 2025

Crystal structure of human aldehyde dehydrogenase 1A3 in complex with selective NR6 inhibitor compound

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.95Å
Ligands:	GOL, NA, NAD, R2K, R2Q
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.

A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro.,Gelardi ELM, Colombo G, Picarazzi F, Ferraris DM, Mangione A, Petrarolo G, Aronica E, Rizzi M, Mori M, La Motta C, Garavaglia S Cancers (Basel). 2021 Jan 19;13(2). pii: cancers13020356. doi:, 10.3390/cancers13020356. PMID:33478031^[1]

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

References

↑ Gelardi ELM, Colombo G, Picarazzi F, Ferraris DM, Mangione A, Petrarolo G, Aronica E, Rizzi M, Mori M, La Motta C, Garavaglia S. A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro. Cancers (Basel). 2021 Jan 19;13(2):356. PMID:33478031 doi:10.3390/cancers13020356

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OCA

[1] Gelardi ELM, Colombo G, Picarazzi F, Ferraris DM, Mangione A, Petrarolo G, Aronica E, Rizzi M, Mori M, La Motta C, Garavaglia S. A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro. Cancers (Basel). 2021 Jan 19;13(2):356. PMID:33478031 doi:10.3390/cancers13020356

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='7a6q' size='340' side='right'caption='[[7a6q]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7a6q]] 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=7A6Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A6Q FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A6Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A6Q FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.95&#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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=R2K:(3-oxidanylidene-3-sodiooxy-propanoyl)oxysodium'>R2K</scene>, <scene name='pdbligand=R2Q:3-(2-phenylimidazo[1,2-a]pyridin-6-yl)benzenecarbonitrile'>R2Q</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=7a6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a6q OCA], [https://pdbe.org/7a6q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a6q RCSB], [https://www.ebi.ac.uk/pdbsum/7a6q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a6q ProSAT]</span></td></tr>
 </table>
-== 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.
-== 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).
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Garavaglia S]]
 [[Category: Gelardi ELM]]

7a6q: Difference between revisions

Latest revision as of 06:29, 1 October 2025

Crystal structure of human aldehyde dehydrogenase 1A3 in complex with selective NR6 inhibitor compound

Structural highlights

Publication Abstract from PubMed

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References

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