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==Crystal structure of human ALDH3A1 with inhibitor 1-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl}-1H-indole-2,3-dione== | ==Crystal structure of human ALDH3A1 with inhibitor 1-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl}-1H-indole-2,3-dione== | ||
<StructureSection load='4l1o' size='340' side='right' caption='[[4l1o]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='4l1o' size='340' side='right'caption='[[4l1o]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4l1o]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L1O OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4l1o]] 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=4L1O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L1O FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1VL:(3S)-1-{[4-(1,3-BENZODIOXOL-5-YLMETHYL)PIPERAZIN-1-YL]METHYL}-3-HYDROXY-1,3-DIHYDRO-2H-INDOL-2-ONE'>1VL</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1VL:(3S)-1-{[4-(1,3-BENZODIOXOL-5-YLMETHYL)PIPERAZIN-1-YL]METHYL}-3-HYDROXY-1,3-DIHYDRO-2H-INDOL-2-ONE'>1VL</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=4l1o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l1o OCA], [https://pdbe.org/4l1o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l1o RCSB], [https://www.ebi.ac.uk/pdbsum/4l1o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l1o ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/AL3A1_HUMAN AL3A1_HUMAN] ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde. They are involved in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. This protein preferentially oxidizes aromatic aldehyde substrates. It may play a role in the oxidation of toxic aldehydes. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure-activity relationships for each ALDH isoenzyme. | |||
Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.,Kimble-Hill AC, Parajuli B, Chen CH, Mochly-Rosen D, Hurley TD J Med Chem. 2014 Feb 13;57(3):714-22. doi: 10.1021/jm401377v. Epub 2014 Jan 31. PMID:24444054<ref>PMID:24444054</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4l1o" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Hurley TD]] | ||
[[Category: | [[Category: Parajuli B]] | ||
Latest revision as of 08:41, 5 June 2024
Crystal structure of human ALDH3A1 with inhibitor 1-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl}-1H-indole-2,3-dioneCrystal structure of human ALDH3A1 with inhibitor 1-{[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]methyl}-1H-indole-2,3-dione
Structural highlights
FunctionAL3A1_HUMAN ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde. They are involved in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. This protein preferentially oxidizes aromatic aldehyde substrates. It may play a role in the oxidation of toxic aldehydes. Publication Abstract from PubMedAldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure-activity relationships for each ALDH isoenzyme. Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.,Kimble-Hill AC, Parajuli B, Chen CH, Mochly-Rosen D, Hurley TD J Med Chem. 2014 Feb 13;57(3):714-22. doi: 10.1021/jm401377v. Epub 2014 Jan 31. PMID:24444054[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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