title: 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.
authors.affiliation: Department of Chemistry, Washington College , Chestertown, Maryland 21620, United States.
authors.forename: James M
authors.initials: JM
authors.lastname: Lipchock
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Heidi P
authors.identifier: http://orcid.org/0000-0002-5012-738X
authors.initials: HP
authors.lastname: Hendrickson
authors.affiliation: Department of Chemistry, Washington College , Chestertown, Maryland 21620, United States.|Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Bonnie B
authors.initials: BB
authors.lastname: Douglas
authors.affiliation: Department of Chemistry, Washington College , Chestertown, Maryland 21620, United States.|Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Bird
authors.affiliation: Department of Chemistry, Washington College , Chestertown, Maryland 21620, United States.|Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Ginther
authors.affiliation: 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.
authors.forename: Ivan
authors.identifier: http://orcid.org/0000-0002-1208-602X
authors.initials: I
authors.lastname: Rivalta
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Ten
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06511, United States.|Department of Molecular Biophysics and Biochemistry, Yale University , New Haven, Connecticut 06511, United States.
authors.forename: J Patrick
authors.identifier: http://orcid.org/0000-0002-4824-9089
authors.initials: JP
authors.lastname: Loria
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation; D001665:Binding Sites; D001667:Binding, Competitive; D002109:Caffeic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D002726:Chlorogenic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013386:Succinates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D013386:Succinates; D002726:Chlorogenic Acid; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C100435:chicoric acid