W0098

Crystal Structure of the B Isoform of the Human Low Molecular Weight Protein Tyrosine Phosphatase. Adam P.R. Zabell¹, Steven Corden¹, Isamu Katsuyama¹, Paul, Helquist², Olaf Wiest², Cynthia V. Stauffacher³, ¹Walther Cancer Institute, Indianapolis, IN, 46208, ²Univ. of Notre Dame, South Bend, IN, 46556, ³Purdue Univ., West Lafayette, IN, 47907.

The human low molecular weight protein tyrosine phosphatase (HCPTP) is ubiquitously expressed as two isoforms in a wide range of human cells. Recent studies have suggested that HCPTP regulates the phosphorylation state of the receptor tyrosine kinase EphA2. This regulation may be significant, as EphA2 is overexpressed in a large number of metastatic human carcinomas and does not demonstrate any tyrosine phosphorylation in aggressively malignant cells, while it is phosphorylated in non-transformed epithelial cells. Our intent to rationally design inhibitory compounds for HCPTP requires a structure for both isoforms. Computational studies based on the known structure of HCPTP-A and a homology model for HCPTP-Bhave indicated that an aromatic ring system with an ethylphosphinate functional group will act as a potent inhibitor.

We have solved the structure for HCPTP-B, which has the same fold seen with other low molecular weight PTPs. Crystals have also been produced with known inhibitors and several novel compounds.