Modeling studies of the interactions between the insulin receptor kinase domain and protein tyrosine phosphatase 1B

The sulfotyrosine peptide, IRK1154, is based on the corresponding phosphoty rosine segment of the insulin receptor kinase domain (IRK) and is a known i nhibitor of the function of the protein tyrosine phosphatase, PTP1B. Two-di mensional NMR spectroscopy, in the transferred nuclear Overhauser effect (N OE) enhancement experiment, was used to obtain information concerning the b ound structure of this peptide. Computer-simulated docking experiments, fol lowed by molecular dynamics simulations in a fully hydrated model, provided information concerning the site-specific interactions influencing the boun d peptide. Using the Structural and orientational information from the NMR studies as a guide, together with the X-ray coordinates for PTP1B and IRK, a detailed model of the binding of these two proteins was developed. The in terface between the two entities is described, and the sites of positive in teractions are identified. Potential sources of destabilizing interactions, necessary for dissociation of the two enzymes, were also found.