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

• Published in: Biochemistry (Easton) Vol. 56; no. 1; pp. 96 - 106
• Main Authors: Lipchock, James M, Hendrickson, Heidi P, Douglas, Bonnie B, Bird, Kelly E, Ginther, Patrick S, Rivalta, Ivan, Ten, Nicholas S, Batista, Victor S, Loria, J. Patrick
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.01.2017
• Subjects: Algorithms; Allosteric Regulation; Binding Sites; Binding, Competitive; Caffeic Acids - chemistry; Caffeic Acids - metabolism; Caffeic Acids - pharmacology; Catalytic Domain; Chemical Sciences; Chlorogenic Acid - chemistry; Chlorogenic Acid - metabolism; Chlorogenic Acid - pharmacology; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Hydrogen Bonding; Kinetics; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Other; Protein Binding; Protein Domains; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Succinates - chemistry; Succinates - metabolism; Succinates - pharmacology
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.6b01025

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.