View source for 9smo


==Crystal Structure of human exonuclease 1 (Exo1) with DNA and compound ART5537==
<StructureSection load='9smo' size='340' side='right'caption='[[9smo]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9smo]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SMO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SMO 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]] 2.199&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JO0:1-(4-chloranyl-2,7-naphthyridin-1-yl)-5-oxidanyl-3-[(1~{S})-1-phenylethyl]-2~{H}-pyrido[2,1-f][1,2,4]triazine-4,6-dione'>A1JO0</scene>, <scene name='pdbligand=GS:GUANOSINE-5-THIO-MONOPHOSPHATE'>GS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PST:THYMIDINE-5-THIOPHOSPHATE'>PST</scene>, <scene name='pdbligand=SC:2-DEOXY-CYTIDINE-5-THIOPHOSPHORATE'>SC</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=9smo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9smo OCA], [https://pdbe.org/9smo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9smo RCSB], [https://www.ebi.ac.uk/pdbsum/9smo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9smo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/EXO1_HUMAN EXO1_HUMAN] 5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.<ref>PMID:10364235</ref> <ref>PMID:10608837</ref> <ref>PMID:11809771</ref> <ref>PMID:11842105</ref> <ref>PMID:12414623</ref> <ref>PMID:12704184</ref> <ref>PMID:14636568</ref> <ref>PMID:14676842</ref> <ref>PMID:15225546</ref> <ref>PMID:15886194</ref> <ref>PMID:16143102</ref> <ref>PMID:9685493</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Exonuclease 1 (EXO1) is emerging as a target of interest in oncology due to its involvement in multifaceted DNA metabolic processes, particularly in homologous recombination (HR). Evidence is building that BRCA1-deficient cancers are sensitive to loss of EXO1, suggesting therapeutic potential for treating certain subsets of patients. However, EXO1 remains under-explored, with very few reported inhibitors, and there is a paucity of good quality, potent, and selective pharmacological tools to explore its biology. Here, we describe a metal-chelating fragment screen, which resulted in highly selective, submicromolar EXO1 hits. Our subsequent structure-based design and optimization led to the discovery of ART5537, the first highly potent and selective EXO1 inhibitor. We demonstrate that inhibition of EXO1 leads to potent suppression of HR in cells and that the HR inhibition of ART5537 is driven exclusively by EXO1. Furthermore, we show that ART5537 sensitizes cancer cells to ionizing radiation (IR) and synergizes with PARP inhibitors (PARPi).

Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1.,Mann SE, Davis OA, Bomke J, Cornaciu I, Elinati E, Follows B, Galbiati A, Geo L, Grande D, Jorand-Lebrun C, Lademann CA, Lefranc J, Leuthner B, Mason B, McWhirter CL, Musil D, Pehl U, Petersson C, Pica A, Pinto MF, Rajendra E, Rakers C, Rego AT, Robinson HMR, Schwarz D, Smith GCM, Sorrell FJ, Zenke FT, Heald RA, Burgdorf LT J Med Chem. 2025 Dec 8. doi: 10.1021/acs.jmedchem.5c02593. PMID:41359073<ref>PMID:41359073</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9smo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Burgdorf L]]
[[Category: Cornaciu I]]
[[Category: Mann SE]]
[[Category: Pica A]]
[[Category: Toste Rego A]]