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Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development

Author

Listed:
  • Navasona Krishnan

    (Cold Spring Harbor Laboratory)

  • Christopher A. Bonham

    (Cold Spring Harbor Laboratory)

  • Ioana A. Rus

    (Cold Spring Harbor Laboratory
    Graduate Program in Genetics and Medical Scientist Training Program, Stony Brook University)

  • Om Kumar Shrestha

    (Cold Spring Harbor Laboratory)

  • Carla M. Gauss

    (Cold Spring Harbor Laboratory)

  • Aftabul Haque

    (Cold Spring Harbor Laboratory)

  • Ante Tocilj

    (Cold Spring Harbor Laboratory
    W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory
    Howard Hughes Medical Institute, Cold Spring Harbor Laboratory)

  • Leemor Joshua-Tor

    (Cold Spring Harbor Laboratory
    W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory
    Howard Hughes Medical Institute, Cold Spring Harbor Laboratory)

  • Nicholas K. Tonks

    (Cold Spring Harbor Laboratory)

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.

Suggested Citation

  • Navasona Krishnan & Christopher A. Bonham & Ioana A. Rus & Om Kumar Shrestha & Carla M. Gauss & Aftabul Haque & Ante Tocilj & Leemor Joshua-Tor & Nicholas K. Tonks, 2018. "Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02252-2
    DOI: 10.1038/s41467-017-02252-2
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