The phosphatase domains of LAR, CD45, and PTP1B: structural correlations with peptide-based inhibitors

PTP1B is a cytosolic protein tyrosine phosphatase that is a regulator of th e kinase activity of the insulin receptor; the two protein tyrosine phospha tases LAR and CD45 are receptor type phosphatases crucially important to ce ll function. LAR also is involved in regulation of the insulin receptor whi le CD45 is critical for T-cell activation. Although LAR and CD45 are both t ransmembrane phosphatases, these enzymes manifest their phosphatase activit y through a catalytic cytosolic domain. We have utilized X-ray coordinates of related phosphatases (RPTP alpha and RPTP mu) and comparative protein mo deling to obtain molecular models of the D1 catalytic domains of CD45 and L AR. The models were tested using established protocols and found to be comp arable to low resolution X-ray structures. The structure obtained for LAR w as compared with the recently reported X-ray structure. Both the CD45-D1 an d LAR-D1 structures were then compared to and contrasted with PTP1B. The ac tive site of pockets of the three enzymes were found to be very uniform in structure and charge distribution. Also, the gross surface topology around the active site was found to be somewhat similar for the 3 phosphatases. Ho wever, there were significant differences in surface topology, and, more im portantly, large changes in surface charge distribution. The differences be tween the surface features of these enzymes provide an explanation for the selectivity of inhibition by a number of peptides.