Krishnan, N., Bonham, C. A., Rus, I. A., Shrestha, O. K., Gauss, C. M., Haque, A., Tocilj, A., Joshua-Tor, L., Tonks, N. K. (January 2018) Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. Nat Commun, 9 (1). p. 283. ISSN 2041-1723
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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 Cancer Center Program > Signal Transduction CSHL labs > Joshua-Tor lab CSHL labs > Tonks lab CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program |
| Depositing User: | Matt Covey |
| Date: | 18 January 2018 |
| Date Deposited: | 25 Jan 2018 22:46 |
| Last Modified: | 13 Nov 2023 20:24 |
| PMCID: | PMC5773487 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35988 |
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