4NAH

Inhibitors of 4-Phosphopanthetheine Adenylyltransferase (PPAT)

4NAH の概要

• エントリーDOI: 10.2210/pdb4nah/pdb
• 関連するPDBエントリー: 4NAT 4NAU
• 分子名称: Phosphopantetheine adenylyltransferase, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, 2-[(2-{(1S,2S)-2-[(3,4-dichlorobenzyl)carbamoyl]cyclohexyl}-6-ethylpyrimidin-4-yl)sulfanyl]-1H-imidazole-5-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: phosphopanthetheine adenylyltransferase, phosphopanthetheine, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Staphylococcus aureus
• 細胞内の位置: Cytoplasm (By similarity): P63820
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 116729.17

構造登録者

Lahiri, S.D. (登録日: 2013-10-22, 公開日: 2014-03-12, 最終更新日: 2024-02-28)

主引用文献

de Jonge, B.L.,Walkup, G.K.,Lahiri, S.D.,Huynh, H.,Neckermann, G.,Utley, L.,Nash, T.J.,Brock, J.,San Martin, M.,Kutschke, A.,Johnstone, M.,Laganas, V.,Hajec, L.,Gu, R.F.,Ni, H.,Chen, B.,Hutchings, K.,Holt, E.,McKinney, D.,Gao, N.,Livchak, S.,Thresher, J.
Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy.
Antimicrob.Agents Chemother., 57:6005-6015, 2013

PubMed Abstract: Inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy.

PubMed: 24041904
DOI: 10.1128/AAC.01661-13

実験手法

X-RAY DIFFRACTION (2.38 Å)