4GFD

Thymidylate kinase (TMK) from S. Aureus in complex with TK-666

4GFD の概要

• エントリーDOI: 10.2210/pdb4gfd/pdb
• 関連するPDBエントリー: 4DWJ 4EAQ 4F4I 4HDC
• 分子名称: 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)
• 機能のキーワード: kinase, thymidine monphosphate, soluble, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Staphylococcus aureus subsp. aureus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48078.17

構造登録者

Olivier, N.B.,Martinez-Botella, G.,Keating, T. (登録日: 2012-08-03, 公開日: 2012-10-24, 最終更新日: 2024-02-28)

主引用文献

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

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: 22908966
DOI: 10.1021/cb300316n

実験手法

X-RAY DIFFRACTION (1.8 Å)