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

1999 ◽  
Vol 77 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Nicholas R Glover ◽  
Alan S Tracey
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modelling ◽  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Nuclear Overhauser Effect ◽  
Tyrosine Phosphatase ◽  
Nmr Studies ◽  
Protein Tyrosine ◽  
Cellular Processes ◽  
Active Site Pocket

The protein tyrosine phosphatases comprise a class of enzymes that are crucial for the regulation of a number of cellular processes. Because of this, they are attracting increasing attention, not only as legitimate therapeutic targets, but also because of their relationship to many fundamental cellular 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 ascertain the bound-state conformation adopted by the 12-amino acid residue casein-derived peptide, CAS200 (NANEEE(sY)SIGSA) and N-terminal truncated forms of this peptide, CAS203 and CAS205. Each of the peptides were found to bind in an extended beta-strand conformation. Extensive molecular modelling and molecular dynamics simulations of the PTP1B/peptide complexes, in a fully hydrated model, allowed a detailed description of the potential sources of the binding interactions to be developed. In agreement with the NMR studies, the modelling provided a picture of binding of CAS200 in which only the central (E203- I208) residues contributed significantly to the binding while the 3 N-terminal and 3 C-terminal residues were quite fluxional. Critical cationic surface residues, lying near to, but outside the active site pocket were the source of strong stabilizing forces that complemented the stabilizing 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.Key words: protein tyrosine phosphatase, PTP1B, casein peptide, inhibitor, NMR structure, molecular modelling, molecular dynamics.

scholarly journals Molecular Dynamics Simulations of A27S and K120A Mutated PTP1B Reveals Selective Binding of the Bidentate Inhibitor

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Xi Chen ◽  
Xia Liu ◽  
Qiang Gan ◽  
Changgen Feng ◽  
Qian Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Tyrosine Phosphatase ◽  
Selective Binding ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Dynamics Simulations

Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.

Synthesis and properties of small molecules designed to covalently capture native and oxidized forms of protein tyrosine phosphatase 1B (PTP1B)

2016 ◽  
Author(s):  
◽  
Kasi Viswanatharaju Ruddraraju
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Tyrosine Phosphatase ◽  
Covalent Modification ◽  
Affinity Labeling ◽  
Protein Tyrosine Phosphatase 1B ◽  
University Of Missouri ◽  
Protein Tyrosine ◽  
Enzyme Active Site ◽  
Carbon Nucleophiles

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Protein tyrosine phosphatase 1B (PTP1B) is a validated target for the treatment of type 2 diabetes and obesity. The discovery of selective inhibitors with drug-like properties has proven to be challenging because there are [about]80 PTP family members that share a similar and positively charged active site. To overcome these challenges, we have pursued two novel approaches for the covalent inactivation of PTP1B. Exo-affinity labeling agents exploit covalent reactions with amino acids outside the enzyme active site to gain both affinity and selectivity. We prepared several affinity labeling agents using a 12-step convergent synthesis. Enzyme assays revealed that some of these agents are capable of inactivating the enzyme by covalent modification. In another project, we prepared a low molecular weight mimic of the oxidized form of PTP1B that is generated in cells, during insulin signaling events. Seeking molecules capable of covalent capture of oxidized PTP1B, we treated this chemical model with several carbon nucleophiles, such as 1,3-diketones and sulfone-stabilized carbon anions. These carbon nucleophiles readily reacted with the model compound, under mild conditions to give stable adducts. Inactivation experiments revealed that 1,3-diketones are capable of inactivating the oxidized PTP1B at micromolar concentrations.

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