View source for 9hlf


==Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH14445==
<StructureSection load='9hlf' size='340' side='right'caption='[[9hlf]], [[Resolution|resolution]] 2.64&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9hlf]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9HLF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HLF 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]] 2.64&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IVU:~{N}-(3,4-dichlorophenyl)pyridin-4-amine'>A1IVU</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9hlf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hlf OCA], [https://pdbe.org/9hlf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hlf RCSB], [https://www.ebi.ac.uk/pdbsum/9hlf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hlf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/OGG1_MOUSE OGG1_MOUSE] DNA repair enzyme that incises DNA at 8-oxoG residues. Excises 7,8-dihydro-8-oxoguanine and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (FAPY) from damaged DNA. Has a beta-lyase activity that nicks DNA 3' to the lesion.
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== Publication Abstract from PubMed ==
8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), which rewrite the biochemical function of the enzyme through redirection of its preferred substrate from 8-oxoG to AP sites. Previously, different ORCA chemotypes were shown to enhance the operational pH window for OGG1, possibly through direct involvement in proton transfer events during DNA strand cleavage. Accordingly, compound pK(a) is a crucial and necessary consideration for the identification and application of future OGG1 ORCAs. Here, we identify a minimal structure of organocatalytic switches-4-anilino pyridines and 6-anilino pyrimidines-which are dimethyl-amino-pyridine (DMAP)-type Bronsted bases binding the active site of OGG1. Systematic interrogation of compound basicity through modulation of electron-withdrawing (EWG) and electron-donating (EDG) substituents reveals that a pK(a) less or equal to the assay pH is a viable parameter for prediction of compound activity. The lead structure (AC(50) 13 nM, pK(a) 7.0) was then identified as a potent scaffold from a screen in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis (MASH), where it reduced hepatic fibrosis by 35%. Collectively, these findings deepen the knowledge of this novel modulator class, with important implications for future enzyme targets and probe development.

Organocatalytic Switches of DNA Glycosylase OGG1 Catalyze a Highly Efficient AP-Lyase Function.,Kehler M, Zhou K, Kemas AM, Del Prado A, Hutchinson ES, Nairn EH, Varga M, Plattner Y, Zhong Y, Purewal-Sidhu O, Haslam J, Wiita E, Gildie H, Singerova K, Szaruga Z, Almlof I, Hormann FM, Liu KC, Wallner O, Ortis F, Homan EJ, Gileadi O, Rudd SG, Stenmark P, de Vega M, Helleday T, D'Arcy-Evans ND, Lauschke VM, Michel M Chemistry. 2025 Apr 28:e202500382. doi: 10.1002/chem.202500382. PMID:40294343<ref>PMID:40294343</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 9hlf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Scaletti Hutchinson E]]
[[Category: Stenmark P]]