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9i57
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 9i57 is ON HOLD Authors: Collie, G.W. Description: Crystal structure of DNPH1 bound by compound 39. Category: Unreleased Structures [[Category:...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of DNPH1 bound by compound 39.== | |
| + | <StructureSection load='9i57' size='340' side='right'caption='[[9i57]], [[Resolution|resolution]] 1.22Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9i57]] 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=9I57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9I57 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]] 1.217Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IZW:3-(3-methoxyphenyl)-4-[[4-[[(3~{S})-1-pyridazin-3-ylpyrrolidin-3-yl]amino]quinazolin-2-yl]amino]benzoic+acid'>A1IZW</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=9i57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9i57 OCA], [https://pdbe.org/9i57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9i57 RCSB], [https://www.ebi.ac.uk/pdbsum/9i57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9i57 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DNPH1_HUMAN DNPH1_HUMAN] Catalyzes the cleavage of the N-glycosidic bond of deoxyribonucleoside 5'-monophosphates to yield deoxyribose 5-phosphate and a purine or pyrimidine base. Deoxyribonucleoside 5'-monophosphates containing purine bases are preferred to those containing pyrimidine bases (By similarity).[HAMAP-Rule:MF_03036] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | DNPH1 is a nucleotide pool sanitizer that cleaves 5-hydroxymethyl-2-deoxyuridine-5-monophosphate (hmdUMP), preventing incorporation of the correspondent non-natural nucleotide into DNA. Recent findings have demonstrated that loss of DNPH1 could potentiate the sensitivity of PARP inhibitors in homologous recombination repair (HRR)-deficient cancers. We report the optimization of a non-nucleoside-based series of DNPH1 inhibitors. Starting from a weak compound 1 (binding affinity pIC(50) 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC(50) 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC(50) 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line. | ||
| - | + | Discovery and Optimization of a Non-Nucleoside-Based Series of Inhibitors of 2'-Deoxynucleoside 5'-Monophosphate Glycosidase (DNPH1).,Barlaam B, Alonso-Crisostomo L, Anderson NA, Argyrou A, Astles PC, Cadogan EB, Carlino L, Collie GW, Davies NL, Hall J, Kitching L, Li X, Michopoulos F, Milbradt AG, Nikkila J, Northall S, O'Connor MJ, Pei X, Shaw J, Slade D, Southgate H, Stead D, Stubbs CJ, Whitehurst BC, Xing B, Yuan Y, Zhou J J Med Chem. 2025 Nov 5. doi: 10.1021/acs.jmedchem.5c02356. PMID:41194588<ref>PMID:41194588</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Collie | + | <div class="pdbe-citations 9i57" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Collie GW]] | ||
Current revision
Crystal structure of DNPH1 bound by compound 39.
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