Krishnan, N., Koveal, D., Miller, D. H., Xue, B., Akshinthala, S. D., Kragelj, J., Jensen, M. R., Gauss, C. M., Page, R., Blackledge, M., Muthuswamy, S. K., Peti, W., Tonks, N. K. (May 2014) Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nature Chemical Biology, 10 (7). pp. 558-566. ISSN 15524450
Abstract
PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > drugs and therapies 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 > Signal Transduction CSHL labs > Muthuswamy lab CSHL labs > Pappin lab CSHL labs > Tonks lab CSHL Cancer Center Shared Resources > Animal Services |
| Depositing User: | Matt Covey |
| Date: | 20 May 2014 |
| Date Deposited: | 09 Jun 2014 16:39 |
| Last Modified: | 29 Oct 2015 18:42 |
| PMCID: | PMC4062594 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30286 |
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