scholarly journals High-resolution crystal structures of the D1 and D2 domains of protein tyrosine phosphatase epsilon for structure-based drug design

2018 ◽  
Vol 74 (10) ◽  
pp. 1015-1026 ◽  
Author(s):  
George T. Lountos ◽  
Sreejith Raran-Kurussi ◽  
Bryan M. Zhao ◽  
Beverly K. Dyas ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Drug Design ◽  
Crystal Structures ◽  
Phosphatase Activity ◽  
Protein Tyrosine Phosphatase ◽  
High Throughput Screening ◽  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Triple Mutant ◽  
Structure Based Drug Design ◽  
Protein Tyrosine

Here, new crystal structures are presented of the isolated membrane-proximal D1 and distal D2 domains of protein tyrosine phosphatase epsilon (PTP∊), a protein tyrosine phosphatase that has been shown to play a positive role in the survival of human breast cancer cells. A triple mutant of the PTP∊ D2 domain (A455N/V457Y/E597D) was also constructed to reconstitute the residues of the PTP∊ D1 catalytic domain that are important for phosphatase activity, resulting in only a slight increase in the phosphatase activity compared with the native D2 protein. The structures reported here are of sufficient resolution for structure-based drug design, and a microarray-based assay for high-throughput screening to identify small-molecule inhibitors of the PTP∊ D1 domain is also described.

scholarly journals Crystal Structure of the Trypanosoma cruzi Protein Tyrosine Phosphatase TcPTP1

2014 ◽  
Vol 70 (a1) ◽  
pp. C824-C824
Author(s):  
George Lountos ◽  
Joseph Tropea ◽  
David Waugh
Keyword(s):  
Crystal Structure ◽  
Drug Design ◽  
Trypanosoma Cruzi ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Large Population ◽  
Protein Tyrosine Phosphatases ◽  
Structure Based Drug Design ◽  
Phosphatase Inhibitors ◽  
Protein Tyrosine

Chagas' disease is a neglected tropical disease transmitted by the flagellated protozoan, Trypanosoma cruzi, which affects millions of people particularly in Latin America. Only two approved drugs are available to treat the disease but they can present several side effects and are not very effective during the chronic stage of the disease. Therefore, given the large population that is at risk, there is a need to discover new molecular targets for drug design efforts. Recently, the T. cruzi protein tyrosine phosphatase, TcPTP1, was shown to play a role in the cellular differentiation and infectivity of the parasite, and therefore, raises its profile as a potential new therapeutic target. Although drug development targeting protein tyrosine phosphatases is challenging and not as advanced as in other targets such as kinases, structure-based drug design methods have shown to be vital in aiding the discovery of novel phosphatase inhibitors with high potency and improved specificity. Here, we present the 2.1 Angstroms resolution X-ray crystal structure of the T. cruzi TcPTP1 that provides structural insights into the active site environment that may be exploited in order to initiate structure-based drug design efforts to develop novel TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also presented that may make it feasible to develop compounds that are specific for TcPTP1.

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