Targeting the disordered C terminus of PTP1B with an allosteric inhibitor

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. (2014) Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nature Chemical Biology, 10 (7). pp. 558-566. ISSN 15524450

URL: http://www.ncbi.nlm.nih.gov/pubmed/24845231
DOI: 10.1038/nchembio.1528

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 Deposited: 09 Jun 2014 16:39
Last Modified: 29 Oct 2015 18:42
PMCID: PMC4062594
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30286

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