Characterization of Protein Tyrosine Phosphatase 1B Inhibition by Chlorogenic Acid and Cichoric Acid

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B. CGA, while a noncompetitive inhibitor, binds in the second aryl phosphate binding site, rather than the predicted benzfuran binding pocket. The molecular dynamics simulations of the apo enzyme and cysteine–phosphoryl intermediate states with and without bound CGA suggest CGA binding inhibits PTP1B by altering hydrogen bonding patterns at the active site. This study provides a mechanistic understanding of the allosteric inhibition of PTP1B.

Abietane-Type Diterpenoids Inhibit Protein Tyrosine Phosphatases by Stabilizing an Inactive Enzyme Conformation

“…This disperse set of residues might suggest that AA binds to multiple sites, but its distribution (five residues appear in flexible loops, and three are buried in regions distal to known binding sites) suggests that changes in protein conformation and/or dynamics are a more likely cause. This effect is consistent with the results of previous NMR analyses, which indicate that the binding of inhibitors to the active site or C-terminal allosteric site (Figure C) can trigger CSPs at both sites and within intermediary regions of the protein; PTP1B thus appears to be quite flexible. , The absence of an obvious binding site for AA (i.e., a clustered set of residues with large CSPs) is surprising but could result from multiple bound conformations; this mode of interaction is compatible with the weak inhibitory effect of AA and with the generally low CSPs (i.e., <0.1 ppm) detected in our experiments . Our NMR results, taken together, indicate that AA modulates the conformation and/or dynamics of PTP1B by adjusting a broadly distributed set of intraprotein interactions that extends beyond its binding site.…”

Twenty years of exceptional success: The molecular education and research consortium in undergraduate computational chemistry (MERCURY)

“…The faculty published 2 peer‐reviewed books, [ 238,239 ] 9 peer‐reviewed book chapters, [ 240–248 ] and 115 peer‐reviewed research papers. [ 249–363 ] This comes to 1.6 peer‐reviewed products/faculty/year during the 3‐year grant period, which is 3.2 times the rate of publication for natural science faculty at PUIs. [ 46 ]…”

The Bioactive Effects of Chicoric Acid As a Functional Food Ingredient

“…Another enzyme, protein tyrosine phosphatase 1B (PTP1B) negatively regulates the insulin signaling pathway by inhibiting the activity of insulin receptor kinase (56). Two studies with molecular docking showed the molecular interactions between the allosteric site of PTP1B and chicoric acid, which suggests chicoric acid might inhibit PTP1B and further activate the insulin signaling pathway (57,58).…”