Harnessing 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) Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. Nat Commun, 9 (1). p. 283. ISSN 2041-1723

URL: https://www.ncbi.nlm.nih.gov/pubmed/29348454
DOI: 10.1038/s41467-017-02252-2

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.

Item Type: Paper
Subjects: diseases & disorders > nutritional and metabolic diseases > diabetes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL labs > Joshua-Tor lab
CSHL labs > Tonks lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date Deposited: 25 Jan 2018 22:46
Last Modified: 13 Jun 2018 16:03
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35988

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving