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Targeting the disordered C terminus of PTP1B with an allosteric inhibitor
- Source :
- Nature Chemical Biology, Nature Chemical Biology, 2014, 10 (7), pp.558-66, Nature Chemical Biology, Nature Publishing Group, 2014, 10 (7), pp.558-66, Nature chemical biology
- Publication Year :
- 2014
- Publisher :
- HAL CCSD, 2014.
-
Abstract
- International audience; 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.
- Subjects :
- Models, Molecular
MESH: Signal Transduction
Receptor, ErbB-2
MESH: Protein Structure, Secondary
MESH: Catalytic Domain
Plasma protein binding
MESH: Allosteric Regulation
Protein Structure, Secondary
Metastasis
Mice
MESH: Protein Structure, Tertiary
0302 clinical medicine
Protein structure
Catalytic Domain
MESH: Molecular Targeted Therapy
MESH: Animals
Molecular Targeted Therapy
MESH: Spermine
MESH: Allosteric Site
MESH: Cholestanes
Protein Tyrosine Phosphatase, Non-Receptor Type 1
0303 health sciences
MESH: Kinetics
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
MESH: Gene Expression Regulation, Neoplastic
Small molecule
3. Good health
Cell biology
Gene Expression Regulation, Neoplastic
MESH: Receptor, ErbB-2
Biochemistry
030220 oncology & carcinogenesis
Female
Signal transduction
Allosteric Site
hormones, hormone substitutes, and hormone antagonists
MESH: Models, Molecular
Protein Binding
Signal Transduction
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
Allosteric regulation
MESH: Mammary Neoplasms, Experimental
Antineoplastic Agents
Breast Neoplasms
Biology
Article
03 medical and health sciences
Allosteric Regulation
medicine
Animals
Humans
MESH: Protein Binding
Binding site
Molecular Biology
MESH: Mice
030304 developmental biology
MESH: Humans
Cholestanes
Mammary Neoplasms, Experimental
Active site
Cell Biology
medicine.disease
Protein Structure, Tertiary
MESH: Protein Tyrosine Phosphatase, Non-Receptor Type 1
Kinetics
biology.protein
MESH: Antineoplastic Agents
Spermine
MESH: Female
MESH: Breast Neoplasms
Subjects
Details
- Language :
- English
- ISSN :
- 15524450 and 15524469
- Database :
- OpenAIRE
- Journal :
- Nature Chemical Biology, Nature Chemical Biology, 2014, 10 (7), pp.558-66, Nature Chemical Biology, Nature Publishing Group, 2014, 10 (7), pp.558-66, Nature chemical biology
- Accession number :
- edsair.doi.dedup.....618e0db7058ee681ab04620ad34e6881