8CG9
Crystal structure of human DNA cross-link repair 1A in complex with a cyclic N-hydroxyurea inhibitor
Summary for 8CG9
| Entry DOI | 10.2210/pdb8cg9/pdb |
| Descriptor | DNA cross-link repair 1A protein, NICKEL (II) ION, 1-[[(3~{R})-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]-3-oxidanyl-thieno[3,2-d]pyrimidine-2,4-dione, ... (7 entities in total) |
| Functional Keywords | dna cross link repair, nuclease inhibition, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40025.16 |
| Authors | Newman, J.A.,Yosaatmadja, Y.,Baddock, H.T.,Bielinski, M.,von Delft, F.,Bountra, C.,McHugh, P.J.,Schofield, C.J.,Gileadi, O. (deposition date: 2023-02-03, release date: 2024-02-21, Last modification date: 2024-09-11) |
| Primary citation | Bielinski, M.,Henderson, L.R.,Yosaatmadja, Y.,Swift, L.P.,Baddock, H.T.,Bowen, M.J.,Brem, J.,Jones, P.S.,McElroy, S.P.,Morrison, A.,Speake, M.,van Boeckel, S.,van Doornmalen, E.,van Groningen, J.,van den Hurk, H.,Gileadi, O.,Newman, J.A.,McHugh, P.J.,Schofield, C.J. Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target. Chem Sci, 15:8227-8241, 2024 Cited by PubMed Abstract: The three human SNM1 metallo-β-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline-hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets. PubMed: 38817593DOI: 10.1039/d4sc00367e PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.68 Å) |
Structure validation
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