Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Anti-Obesity Agents / chemistry*
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Anti-Obesity Agents / metabolism
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Benzophenanthridines / chemistry
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Benzophenanthridines / metabolism
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Binding Sites
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Cloning, Molecular
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Humans
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / metabolism
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Insulin / chemistry
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Insulin / metabolism
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Isoquinolines / chemistry
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Isoquinolines / metabolism
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Leptin / chemistry
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Leptin / metabolism
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Levamisole / chemistry
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Levamisole / metabolism
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Molecular Docking Simulation
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Oxidation-Reduction
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Structure, Secondary
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Single-Chain Antibodies / chemistry*
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Single-Chain Antibodies / genetics
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Single-Chain Antibodies / metabolism
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Small Molecule Libraries / chemistry*
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Small Molecule Libraries / metabolism
Substances
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Anti-Obesity Agents
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Benzophenanthridines
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Enzyme Inhibitors
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Hypoglycemic Agents
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Insulin
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Isoquinolines
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Leptin
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Recombinant Proteins
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Single-Chain Antibodies
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Small Molecule Libraries
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Levamisole
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sanguinarine
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chelerythrine
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1