Format

Send to

Choose Destination
Nat Chem Biol. 2014 Jul;10(7):558-66. doi: 10.1038/nchembio.1528. Epub 2014 May 20.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
2
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
3
1] Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA. [2] Department of Chemistry, Brown University, Providence, Rhode Island, USA.
4
1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2].
5
Protein Dynamics and Flexibility, Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, Grenoble, France.
6
1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2] Department of Medical Biophysics, Ontario Cancer Institute, Campbell Family Institute for Breast Cancer Research, University of Toronto, Toronto, Canada.

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.

PMID:
24845231
PMCID:
PMC4062594
DOI:
10.1038/nchembio.1528
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center