Download MendeleyHarnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.
Krishnan, N., Bonham, C.A., Rus, I.A., Shrestha, O.K., Gauss, C.M., Haque, A., Tocilj, A., Joshua-Tor, L., Tonks, N.K.(2018) Nat Commun 9: 283-283
- PubMed: 29348454
- DOI: https://doi.org/10.1038/s41467-017-02252-2
- Primary Citation of Related Structures:
5VF6 - PubMed 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.
Organizational Affiliation:
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA.
