| Structural highlights
9seb is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.9Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
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[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Qiu J, Qian Y, Chen V, Guan MX, Shen B. Human exonuclease 1 functionally complements its yeast homologues in DNA recombination, RNA primer removal, and mutation avoidance. J Biol Chem. 1999 Jun 18;274(25):17893-900. PMID:10364235
- ↑ Lee BI, Wilson DM 3rd. The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities. J Biol Chem. 1999 Dec 31;274(53):37763-9. PMID:10608837
- ↑ Genschel J, Bazemore LR, Modrich P. Human exonuclease I is required for 5' and 3' mismatch repair. J Biol Chem. 2002 Apr 12;277(15):13302-11. Epub 2002 Jan 24. PMID:11809771 doi:http://dx.doi.org/10.1074/jbc.M111854200
- ↑ Lee Bi BI, Nguyen LH, Barsky D, Fernandes M, Wilson DM 3rd. Molecular interactions of human Exo1 with DNA. Nucleic Acids Res. 2002 Feb 15;30(4):942-9. PMID:11842105
- ↑ Sun X, Zheng L, Shen B. Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome. Cancer Res. 2002 Nov 1;62(21):6026-30. PMID:12414623
- ↑ Sharma S, Sommers JA, Driscoll HC, Uzdilla L, Wilson TM, Brosh RM Jr. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. J Biol Chem. 2003 Jun 27;278(26):23487-96. Epub 2003 Apr 18. PMID:12704184 doi:http://dx.doi.org/10.1074/jbc.M212798200
- ↑ Genschel J, Modrich P. Mechanism of 5'-directed excision in human mismatch repair. Mol Cell. 2003 Nov;12(5):1077-86. PMID:14636568
- ↑ Nielsen FC, Jager AC, Lutzen A, Bundgaard JR, Rasmussen LJ. Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA. Oncogene. 2004 Feb 19;23(7):1457-68. PMID:14676842 doi:http://dx.doi.org/10.1038/sj.onc.1207265
- ↑ Dzantiev L, Constantin N, Genschel J, Iyer RR, Burgers PM, Modrich P. A defined human system that supports bidirectional mismatch-provoked excision. Mol Cell. 2004 Jul 2;15(1):31-41. PMID:15225546 doi:http://dx.doi.org/10.1016/j.molcel.2004.06.016
- ↑ Doherty KM, Sharma S, Uzdilla LA, Wilson TM, Cui S, Vindigni A, Brosh RM Jr. RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination. J Biol Chem. 2005 Jul 29;280(30):28085-94. Epub 2005 May 9. PMID:15886194 doi:http://dx.doi.org/10.1074/jbc.M500265200
- ↑ Zhang Y, Yuan F, Presnell SR, Tian K, Gao Y, Tomkinson AE, Gu L, Li GM. Reconstitution of 5'-directed human mismatch repair in a purified system. Cell. 2005 Sep 9;122(5):693-705. PMID:16143102 doi:http://dx.doi.org/10.1016/j.cell.2005.06.027
- ↑ Wilson DM 3rd, Carney JP, Coleman MA, Adamson AW, Christensen M, Lamerdin JE. Hex1: a new human Rad2 nuclease family member with homology to yeast exonuclease 1. Nucleic Acids Res. 1998 Aug 15;26(16):3762-8. PMID:9685493
- ↑ 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, Rêgo AT, Robinson HMR, Schwarz D, Smith GCM, Sorrell FJ, Zenke FT, Heald RA, Burgdorf LT. Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1. J Med Chem. 2025 Dec 8. PMID:41359073 doi:10.1021/acs.jmedchem.5c02593
|
