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

Author:

Lountos, George

Raran-Kurussi, Sreejith

Zhao, Bryan M

Dyas, Beverly K

Burke, Terrence

Ulrich, Robert G

Waugh, David
Author Address

Basic Science Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA., Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., The Oak Ridge Institute for Science and Education, Oak Ridge, TN 37831, USA., Molecular and Translational Sciences Division, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA., Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.,

Abstract:

Here, new crystal structures are presented of the isolated membrane-proximal D1 and distal D2 domains of protein tyrosine phosphatase epsilon (PTPE), 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 PTPE D2 domain (A455N/V457Y/E597D) was also constructed to reconstitute the residues of the PTPE 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 PTPE D1 domain is also described.

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