leptin and sanguinarine

The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity. Nevertheless, it is a challenging target for inhibitor development. Previously, we generated a recombinant antibody (scFv45) that recognizes selectively the oxidized, inactive conformation of PTP1B. Here, we provide a molecular basis for its interaction with reversibly oxidized PTP1B. Furthermore, we have identified a small molecule inhibitor that mimics the effects of scFv45. Our data provide proof-of-concept that stabilization of PTP1B in an inactive, oxidized conformation by small molecules can promote insulin and leptin signaling. This work illustrates a novel paradigm for inhibiting the signaling function of PTP1B that may be exploited for therapeutic intervention in diabetes and obesity.

Topics: Amino Acid Sequence; Anti-Obesity Agents; Benzophenanthridines; Binding Sites; Cloning, Molecular; Crystallography, X-Ray; Enzyme Inhibitors; Escherichia coli; Gene Expression; Humans; Hypoglycemic Agents; Insulin; Isoquinolines; Leptin; Levamisole; Molecular Docking Simulation; Oxidation-Reduction; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Recombinant Proteins; Single-Chain Antibodies; Small Molecule Libraries