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Biochemistry. 2017 Jan 10;56(1):96-106. doi: 10.1021/acs.biochem.6b01025. Epub 2016 Dec 27.

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

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Department of Chemistry, Washington College , Chestertown, Maryland 21620, United States.
Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
Univ Lyon, Ens de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie UMR 5182 , F-69342, Lyon, France.
Department of Molecular Biophysics and Biochemistry, Yale University , New Haven, Connecticut 06511, United States.


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.

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