Structure, modelling, and molecular dynamics studies of the inhibition of protein tyrosine phosphatase 1B by sulfotyrosine peptides

The protein tyrosine phosphatases comprise a class of enzymes that are cruc ial for the regulation of a number of cellular processes. Because of this, they are attracting increasing attention, not only as legitimate therapeuti c targets, but also because of their relationship to many fundamental cellu lar processes. Certain sulfotyrosine peptides derived from casein are known to be good inhibitors of the protein tyrosine phosphatase, PTP1B. In this study, NMR transfer nuclear Overhauser effect studies have been used to asc ertain the bound-state conformation adopted by the 12-amino acid residue ca sein-derived peptide, CAS200 (NANEEE(sY)SIGSA) and N-terminal truncated for ms of this peptide, CAS203 and CAS205. Each of the peptides were found to b ind in an extended beta-strand conformation. Extensive molecular modelling and molecular dynamics simulations of the PTP1B/peptide complexes, in a ful ly hydrated model, allowed a detailed description of the potential sources of the binding interactions to be developed. In agreement with the NMR stud ies, the modelling provided a picture of binding of CAS200 in which only th e central (E203- I208) residues contributed significantly to the binding wh ile the 3 N-terminal and 3 C-terminal residues were quite fluxional. Critic al cationic surface residues, lying near to, but outside the active site po cket were the source of strong stabilizing forces that complemented the sta bilizing interactions of the active site pocket. Electrostatic, hydrophobic , and hydrogen bonding interactions, in a residue specific manner, were all found to make significant contributions to the binding of these inhibitors .