View source for 9da2


==Crystal structure of human DNPH1 bound to inhibitor 1b==
<StructureSection load='9da2' size='340' side='right'caption='[[9da2]], [[Resolution|resolution]] 1.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9da2]] 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=9DA2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DA2 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]] 1.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BBC:[(2~{R},3~{R},4~{S},5~{R})-4-fluoranyl-5-[5-(hydroxymethyl)-2,4-bis(oxidanylidene)pyrimidin-1-yl]-3-oxidanyl-oxolan-2-yl]methyl+dihydrogen+phosphate'>A1BBC</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=9da2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9da2 OCA], [https://pdbe.org/9da2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9da2 RCSB], [https://www.ebi.ac.uk/pdbsum/9da2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9da2 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]
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== Publication Abstract from PubMed ==
DNPH1 is responsible for eliminating the epigenetically modified nucleotide, 5-hydroxymethyl-2'-deoxyuridine 5'-monophosphate (hmdUMP), preventing formation of hmdUTP, a mutation-inducing nucleotide. Loss of DNPH1 activity sensitizes PARP inhibition-resistant BRCA-deficient cancers by causing incorporation of hmdUTP into DNA. Hydrolysis of hmdUMP by DNPH1 proceeds through a covalent intermediate between Glu104 and 2-deoxyribose 5-phosphate, followed by hydrolysis, a reaction cycle with two transition states. We describe synthesis and characterization of transition state mimics for both transition states of DNPH1. Both transition states prefer inhibitors with cationic charge at the anomeric center and provide a foundation for inhibitor design. Ground-state complexes show reaction coordinate nucleophiles poised 3.3-3.7 A from the anomeric carbon while transition state analogs tighten the reaction coordinate to place the nucleophiles 2.7-2.8 A from the anomeric carbon. Crystal structures of DNPH1 with transition state analogs reveal transition states where the electrophilic ribocation migrates between the leaving groups and attacking nucleophiles.

Transition State Analogs of Human DNPH1 Reveal Two Electrophile Migration Mechanisms.,Wagner AG, Lang TBD, Ledingham ET, Ghosh A, Brooks D, Eskandari R, Suthagar K, Almo SC, Lamiable-Oulaidi F, Tyler PC, Schramm VL J Med Chem. 2025 Jan 16. doi: 10.1021/acs.jmedchem.4c02778. PMID:39818772<ref>PMID:39818772</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9da2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Almo SC]]
[[Category: Ghosh A]]
[[Category: Schramm VL]]
[[Category: Wagner AG]]