5CDO
3.15A structure of QPT-1 with S.aureus DNA gyrase and DNA
Summary for 5CDO
| Entry DOI | 10.2210/pdb5cdo/pdb |
| Descriptor | DNA gyrase subunit A, (2R,4S,4aS,5R)-6'-hydroxy-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4'(3'H)-dione, DNA gyrase subunit B,DNA gyrase subunit B, ... (11 entities in total) |
| Functional Keywords | type iia topoisomerase, antibacterial, inhibitor, isomerase |
| Biological source | Staphylococcus aureus (strain N315) More |
| Cellular location | Cytoplasm : Q99XG5 |
| Total number of polymer chains | 12 |
| Total formula weight | 330738.20 |
| Authors | Bax, B.D.,Srikannathasan, V.,Chan, P.F. (deposition date: 2015-07-04, release date: 2015-12-16, Last modification date: 2024-11-20) |
| Primary citation | Chan, P.F.,Srikannathasan, V.,Huang, J.,Cui, H.,Fosberry, A.P.,Gu, M.,Hann, M.M.,Hibbs, M.,Homes, P.,Ingraham, K.,Pizzollo, J.,Shen, C.,Shillings, A.J.,Spitzfaden, C.E.,Tanner, R.,Theobald, A.J.,Stavenger, R.A.,Bax, B.D.,Gwynn, M.N. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nat Commun, 6:10048-10048, 2015 Cited by PubMed Abstract: New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PubMed: 26640131DOI: 10.1038/ncomms10048 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.15 Å) |
Structure validation
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