4GFD
Thymidylate kinase (TMK) from S. Aureus in complex with TK-666
Summary for 4GFD
| Entry DOI | 10.2210/pdb4gfd/pdb |
| Related | 4DWJ 4EAQ 4F4I 4HDC |
| Descriptor | Thymidylate kinase, 2-(3-bromophenoxy)-4-{(1R)-3,3-dimethyl-1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]butyl}benzoic acid (3 entities in total) |
| Functional Keywords | kinase, thymidine monphosphate, soluble, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Staphylococcus aureus subsp. aureus |
| Total number of polymer chains | 2 |
| Total formula weight | 48078.17 |
| Authors | Olivier, N.B.,Martinez-Botella, G.,Keating, T. (deposition date: 2012-08-03, release date: 2012-10-24, Last modification date: 2024-02-28) |
| Primary citation | Keating, T.A.,Newman, J.V.,Olivier, N.B.,Otterson, L.G.,Andrews, B.,Boriack-Sjodin, P.A.,Breen, J.N.,Doig, P.,Dumas, J.,Gangl, E.,Green, O.M.,Guler, S.Y.,Hentemann, M.F.,Joseph-McCarthy, D.,Kawatkar, S.,Kutschke, A.,Loch, J.T.,McKenzie, A.R.,Pradeepan, S.,Prasad, S.,Martinez-Botella, G. In Vivo Validation of Thymidylate Kinase (TMK) with a Rationally Designed, Selective Antibacterial Compound. Acs Chem.Biol., 7:1866-1872, 2012 Cited by PubMed Abstract: There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK. PubMed: 22908966DOI: 10.1021/cb300316n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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