4GSY

Crystal structure of thymidylate kinase from Staphylococcus aureus bound to inhibitor.

Summary for 4GSY

• Entry DOI: 10.2210/pdb4gsy/pdb
• Related: 4F4I 4HDC 4HEJ
• Descriptor: Thymidylate kinase, 4-{[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]methyl}-2-[3-(trifluoromethyl)phenoxy]benzoic acid (3 entities in total)
• Functional Keywords: transferase, nucleotide binding, thymidylate kinase activity, atp binding, kinase activity, transferase activity, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Staphylococcus aureus subsp. aureus
• Total number of polymer chains: 2
• Total formula weight: 47916.11

Authors

Larsen, N.A.,Olivier, N.B. (deposition date: 2012-08-28, release date: 2012-10-24, Last modification date: 2024-02-28)

Primary citation

Martinez-Botella, G.,Breen, J.N.,Duffy, J.E.,Dumas, J.,Geng, B.,Gowers, I.K.,Green, O.M.,Guler, S.,Hentemann, M.F.,Hernandez-Juan, F.A.,Joseph-McCarthy, D.,Kawatkar, S.,Larsen, N.A.,Lazari, O.,Loch, J.T.,Macritchie, J.A.,McKenzie, A.R.,Newman, J.V.,Olivier, N.B.,Otterson, L.G.,Owens, A.P.,Read, J.,Sheppard, D.W.,Keating, T.A.
Discovery of Selective and Potent Inhibitors of Gram-Positive Bacterial Thymidylate Kinase (TMK).
J.Med.Chem., 55:10010-10021, 2012

PubMed Abstract: Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.

PubMed: 23043329
DOI: 10.1021/jm3011806

Experimental method

X-RAY DIFFRACTION (1.71 Å)