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

Acta Crystallogr D Struct Biol. 2018 Oct 1;74(Pt 10):1015-1026. doi: 10.1107/S2059798318011919. Epub 2018 Oct 2.

Abstract

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

Keywords: PTP; RPTP; microarray assay; protein tyrosine phosphatase; receptor-like protein tyrosine phosphatase; structure-based drug design.

MeSH terms

  • Crystallography, X-Ray / methods
  • Drug Design*
  • Humans
  • Protein Array Analysis / methods*
  • Protein Domains / genetics*
  • Protein Structure, Tertiary
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / chemistry*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4 / genetics
  • Small Molecule Libraries

Substances

  • Small Molecule Libraries
  • Receptor-Like Protein Tyrosine Phosphatases, Class 4