View source for 7jws


==Crystal structure of human ALDH1A1 bound to compound (R)-28==
<StructureSection load='7jws' size='340' side='right'caption='[[7jws]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7jws]] is a 1 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=7JWS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JWS 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]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=VLY:1-methyl-5-phenyl-6-{[(1R)-1-phenylethyl]sulfanyl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one'>VLY</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</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=7jws FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jws OCA], [https://pdbe.org/7jws PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jws RCSB], [https://www.ebi.ac.uk/pdbsum/7jws PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jws ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AL1A1_HUMAN AL1A1_HUMAN] Binds free retinal and cellular retinol-binding protein-bound retinal. Can convert/oxidize retinaldehyde to retinoic acid (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued development of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in this critical tumor subtype. Optimization of the CM39 scaffold, aided by metabolite ID and several new ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular ALDH inhibition in HGSOC cell lines, and substantial improvements in microsomal stability culminating in orally bioavailable compounds. We demonstrate that two compounds 68 and 69 are able to synergize with chemotherapy in a resistant cell line and patient-derived HGSOC tumor spheroids, indicating their suitability for future in vivo proof of concept experiments.

Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy.,Huddle BC, Grimley E, Chtcherbinine M, Buchman CD, Takahashi C, Debnath B, McGonigal SC, Mao S, Li S, Felton J, Pan S, Wen B, Sun D, Neamati N, Buckanovich RJ, Hurley TD, Larsen SD Eur J Med Chem. 2020 Dec 3;211:113060. doi: 10.1016/j.ejmech.2020.113060. PMID:33341649<ref>PMID:33341649</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7jws" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Buchman C]]
[[Category: Hurley TD]]