Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29348454.
- Also identified by DOI 10.1038/s41467-017-02252-2 and PMC identifier 5773487.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Anti-Obesity Agents
- Enzyme Inhibitors
- Hypoglycemic Agents
- Protein Tyrosine Phosphatase, Non-Receptor Type 1
- Single-Chain Antibodies
- Small Molecule Libraries