2Y2F
Crystal structure of Yersinia pestis YopH in complex with an aminooxy- containing platform compound for inhibitor design
Summary for 2Y2F
| Entry DOI | 10.2210/pdb2y2f/pdb |
| Related | 1QZ0 |
| Descriptor | PROTEIN-TYROSINE PHOSPHATASE YOPH, [4-[3-(DIFLUORO-PHOSPHONO-METHYL)PHENYL]PHENYL]METHOXYAZANIUM (3 entities in total) |
| Functional Keywords | hydrolase, protein tyrosine phosphatase |
| Biological source | YERSINIA PESTIS |
| Total number of polymer chains | 1 |
| Total formula weight | 33884.13 |
| Authors | Lountos, G.T.,Bahta, M.,Dyas, B.,Ulrich, R.G.,Waugh, D.S.,Burke, T.R. (deposition date: 2010-12-14, release date: 2011-03-16, Last modification date: 2023-12-20) |
| Primary citation | 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 Cited by 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: 21443195DOI: 10.1021/JM200022G PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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