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Targeting the disordered C terminus of PTP1B with an allosteric inhibitor.

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.
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Contributor : Frank Thomas <>
Submitted on : Friday, March 13, 2015 - 8:44:01 AM
Last modification on : Wednesday, April 7, 2021 - 3:18:07 PM

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Navasona Krishnan, Dorothy Koveal, Daniel H Miller, Bin Xue, Sai Dipikaa Akshinthala, et al.. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor.. Nature Chemical Biology, Nature Publishing Group, 2014, 10 (7), pp.558-66. ⟨hal-01131138⟩



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