期刊
NATURE CHEMICAL BIOLOGY
卷 10, 期 7, 页码 558-566出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1528
关键词
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资金
- US National Institutes of Health (NIH) [CA53840, GM55989]
- Cold Spring Harbor Laboratory Cancer Centre Support Grant [CA45508]
- NIH [GM100910, GM098482, S10-RR017269]
- American Diabetes Association [1-14-ACN-31]
- Brown University Research Seed Fund grant
- French Agence Nationale de la Recherche (ANR) through ANR JCJC ProteinDisorder
- ANR MALZ TAUSTRUCT
- IDPbyNMR Marie Curie action of the European Commission [264257]
- Gladowsky Breast Cancer Foundation
- Don Monti Memorial Research Foundation
- Hansen Memorial Foundation
- West Islip Breast Cancer Coalition
- Glen Cove CARES
- Constance Silveri, Robertson Research Fund
- Masthead Cove Yacht Club Carol Marcincuk Fund
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.
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