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==ALDH1A2 liganded with NAD and compound WIN18,446==
<StructureSection load='6alj' size='340' side='right'caption='[[6alj]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6alj]] 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=6ALJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ALJ 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]] 1.89&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CW2:N,N-(octane-1,8-diyl)bis(2,2-dichloroacetamide)'>CW2</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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=6alj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6alj OCA], [https://pdbe.org/6alj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6alj RCSB], [https://www.ebi.ac.uk/pdbsum/6alj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6alj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AL1A2_HUMAN AL1A2_HUMAN] Recognizes as substrates free retinal and cellular retinol-binding protein-bound retinal. Does metabolize octanal and decanal but does not metabolize citral, benzaldehyde, acetaldehyde and propanal efficiently (By similarity).
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== Publication Abstract from PubMed ==
Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in (R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles.

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors.,Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK, Schonbrunn E ACS Chem Biol. 2018 Jan 3. doi: 10.1021/acschembio.7b00685. PMID:29240402<ref>PMID:29240402</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6alj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen Y]]
[[Category: Schonbrunn E]]
[[Category: Zhu J-Y]]