7zc7: Difference between revisions
New page: '''Unreleased structure''' The entry 7zc7 is ON HOLD Authors: Description: Category: Unreleased Structures |
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==Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH012941== | |||
<StructureSection load='7zc7' size='340' side='right'caption='[[7zc7]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7zc7]] 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=7ZC7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZC7 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]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IKL:2-[4-(3,5-dimethylpyrazol-1-yl)phenyl]-~{N}-(4,5,6,7-tetrahydro-1,2-benzoxazol-3-yl)ethanamide'>IKL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=7zc7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zc7 OCA], [https://pdbe.org/7zc7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zc7 RCSB], [https://www.ebi.ac.uk/pdbsum/7zc7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zc7 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 10(22) compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets. | |||
Virtual fragment screening for DNA repair inhibitors in vast chemical space.,Luttens A, Vo DD, Scaletti ER, Wiita E, Almlof I, Wallner O, Davies J, Kosenina S, Meng L, Long M, Mortusewicz O, Masuyer G, Ballante F, Michel M, Homan E, Scobie M, Kalderen C, Warpman Berglund U, Tarnovskiy AV, Radchenko DS, Moroz YS, Kihlberg J, Stenmark P, Helleday T, Carlsson J Nat Commun. 2025 Feb 18;16(1):1741. doi: 10.1038/s41467-025-56893-9. PMID:39966348<ref>PMID:39966348</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7zc7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Davies JR]] | |||
[[Category: Scaletti E]] | |||
[[Category: Stenmark P]] | |||
Latest revision as of 11:28, 5 March 2025
Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH012941Structure of the mouse 8-oxoguanine DNA Glycosylase mOGG1 in complex with ligand TH012941
Structural highlights
FunctionOGG1_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. Publication Abstract from PubMedFragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 10(22) compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets. Virtual fragment screening for DNA repair inhibitors in vast chemical space.,Luttens A, Vo DD, Scaletti ER, Wiita E, Almlof I, Wallner O, Davies J, Kosenina S, Meng L, Long M, Mortusewicz O, Masuyer G, Ballante F, Michel M, Homan E, Scobie M, Kalderen C, Warpman Berglund U, Tarnovskiy AV, Radchenko DS, Moroz YS, Kihlberg J, Stenmark P, Helleday T, Carlsson J Nat Commun. 2025 Feb 18;16(1):1741. doi: 10.1038/s41467-025-56893-9. PMID:39966348[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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