2Y2F

Crystal structure of Yersinia pestis YopH in complex with an aminooxy- containing platform compound for inhibitor design

2Y2F の概要

• エントリーDOI: 10.2210/pdb2y2f/pdb
• 関連するPDBエントリー: 1QZ0
• 分子名称: PROTEIN-TYROSINE PHOSPHATASE YOPH, [4-[3-(DIFLUORO-PHOSPHONO-METHYL)PHENYL]PHENYL]METHOXYAZANIUM (3 entities in total)
• 機能のキーワード: hydrolase, protein tyrosine phosphatase
• 由来する生物種: YERSINIA PESTIS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33884.13

構造登録者

Lountos, G.T.,Bahta, M.,Dyas, B.,Ulrich, R.G.,Waugh, D.S.,Burke, T.R. (登録日: 2010-12-14, 公開日: 2011-03-16, 最終更新日: 2023-12-20)

主引用文献

Bahta, M.,Lountos, G.T.,Dyas, B.,Kim, S.,Ulrich, R.G.,Waugh, D.S.,Burke, T.R.
Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia Pestis Outer Protein H (Yoph) Phosphatase.
J.Med.Chem., 54:2933-, 2011

PubMed Abstract: Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 μM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.

PubMed: 21443195
DOI: 10.1021/JM200022G

実験手法

X-RAY DIFFRACTION (1.78 Å)