title: Development of accessible peptidic tool compounds to study the phosphatase PTP1B in intact cells.
abstract: Protein tyrosine phosphatases (PTPs) play crucial roles in health and disease. Chemical modulators of their activity are vital tools to study their function. An important aspect is the accessibility of these tools, which is usually limited or not existent due to the required, often complex synthesis of the molecules. We describe here a strategy for the development of cellular active inhibitors and in-cell detection tools for PTP1B as a model PTP, which plays important roles in diabetes, obesity, and cancer. The tool compounds are based on a peptide sequence from PTP1B's substrate Src, and the resulting compounds are commercially accessible through standard peptide synthesis. The peptide inhibitor is remarkably selective against a panel of PTPs. We provide the co-crystal structure of PTP1B with the sequence from Src and the optimized peptide inhibitor, showing the molecular basis of the interaction of PTP1B with part of its natural substrate and explaining the crucial interactions to enhance binding affinity, which are made possible by simple optimization of the sequence. Our approach enables the broad accessibility of PTP1B tools to researchers and has the potential for the systematic development of accessible PTP modulators to enable the study of PTPs.
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory , Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meyer
authors.forename: Birgit
authors.initials: B
authors.lastname: Hoeger
authors.forename: Koen
authors.initials: K
authors.lastname: Temmerman
authors.forename: Marianna
authors.initials: M
authors.lastname: Tatarek-Nossol
authors.forename: Vivian
authors.initials: V
authors.lastname: Pogenberg
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.forename: Matthias
authors.initials: M
authors.lastname: Wilmanns
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Kapurniotu
authors.forename: Maja
authors.initials: M
authors.lastname: Köhn
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000633:toxicity; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000633:toxicity; D005454:Fluorescence Polarization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D004791:Enzyme Inhibitors; D010455:Peptides; C015462:polyarginine; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1