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

Navasona Krishnan, Christopher A. Bonham, Ioana A. Rus, Om Kumar Shrestha, Carla M. Gauss, Aftabul Haque, Ante Tocilj, Leemor Joshua-Tor and Nicholas K. Tonks ()
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Navasona Krishnan: Cold Spring Harbor Laboratory
Christopher A. Bonham: Cold Spring Harbor Laboratory
Ioana A. Rus: Cold Spring Harbor Laboratory
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
Leemor Joshua-Tor: Cold Spring Harbor Laboratory
Nicholas K. Tonks: Cold Spring Harbor Laboratory

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02252-2

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