9rur

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Current revision (09:24, 22 October 2025) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 9rur is ON HOLD until Paper Publication
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==Structure of WRN in complex with ATPgS and covalent ligand Compound 4d==
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<StructureSection load='9rur' size='340' side='right'caption='[[9rur]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[9rur]] 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=9RUR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9RUR FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.296&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JJK:2-ethylsulfanyl-~{N}-[1-[(4-fluorophenyl)methyl]indazol-3-yl]ethanamide'>A1JJK</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9rur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9rur OCA], [https://pdbe.org/9rur PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9rur RCSB], [https://www.ebi.ac.uk/pdbsum/9rur PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9rur ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/WRN_HUMAN WRN_HUMAN] Defects in WRN are a cause of Werner syndrome (WRN) [MIM:[https://omim.org/entry/277700 277700]. WRN is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. Currently all known WS mutations produces prematurely terminated proteins.<ref>PMID:16673358</ref> Defects in WRN may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].
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== Function ==
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[https://www.uniprot.org/uniprot/WRN_HUMAN WRN_HUMAN] Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity).<ref>PMID:11863428</ref> <ref>PMID:17563354</ref> <ref>PMID:18596042</ref> <ref>PMID:19652551</ref> <ref>PMID:19283071</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Werner (WRN) helicase, has emerged as a promising therapeutic target for cancers associated with microsatellite instability (MSI). This letter describes the discovery of small molecule inhibitors from a fragment screen that occupy a cryptic, allosteric site of WRN helicase. Key findings include the identification of benzimidazole and amino-indazole scaffolds, exploiting their proximity to Cys727 via covalent modification. The use of our proprietary co-folding model DragonFold assisted the identification of novel WRN helicase inhibitors. These, together with near-neighbor profiling, offer tools for furthering the understanding of WRN and BLM helicase function, and potential therapeutic avenues for MSI-associated cancers.
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Authors:
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AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen.,Smith GMT, Aithani L, Barrett CE, Bucher AO, Cooper CDO, Degorce SL, Dore AS, Fletcher CT, Huber S, Huckvale R, Kennedy AJ, Mornement AA, Pickworth M, Rucktooa P, Scully CCG, Skerratt SE Bioorg Med Chem Lett. 2025 Sep 30:130421. doi: 10.1016/j.bmcl.2025.130421. PMID:41038585<ref>PMID:41038585</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 9rur" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Fletcher CT]]
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[[Category: Rucktooa P]]

Current revision

Structure of WRN in complex with ATPgS and covalent ligand Compound 4d

PDB ID 9rur

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