Targeting the disordered C terminus of PTP1B with an allosteric inhibitor.
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.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Navasona
N
Krishnan
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Dorothy
D
Koveal
1] Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA. [2] Department of Chemistry, Brown University, Providence, Rhode Island, USA.
Daniel H
DH
Miller
1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2].
Bin
B
Xue
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Sai Dipikaa
SD
Akshinthala
Protein Dynamics and Flexibility, Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, Grenoble, France.
Jaka
J
Kragelj
Protein Dynamics and Flexibility, Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, Grenoble, France.
Malene Ringkjøbing
MR
Jensen
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Carla-Maria
CM
Gauss
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Rebecca
R
Page
Protein Dynamics and Flexibility, Institut de Biologie Structurale Jean-Pierre Ebel, CEA, CNRS, Grenoble, France.
Martin
M
Blackledge
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.
Senthil K
SK
Muthuswamy
1] Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA. [2] Department of Chemistry, Brown University, Providence, Rhode Island, USA.
Wolfgang
W
Peti
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Nicholas K
NK
Tonks
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020134:Catalytic Domain; D002776:Cholestanes / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D002776:Cholestanes; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D013096:Spermine; C441128:3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate; C508053:ERBB2 protein, human; C516607:PTPN1 protein, human