Development of accessible peptidic tool compounds to study the phosphatase PTP1B in intact cells

TY - JOUR

T1 - Development of accessible peptidic tool compounds to study the phosphatase PTP1B in intact cells

AU - Meyer, Christoph

AU - Hoeger, Birgit

AU - Temmerman, Koen

AU - Tatarek-Nossol, Marianna

AU - Pogenberg, Vivian

AU - Bernhagen, Jürgen

AU - Wilmanns, Matthias

AU - Kapurniotu, Aphrodite

AU - Köhn, Maja

PY - 2014/3/21

Y1 - 2014/3/21

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Binding Sites

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Cell-Penetrating Peptides/chemistry

KW - Computational Biology/methods

KW - Crystallography, X-Ray

KW - Enzyme Inhibitors/chemistry

KW - Fluorescence Polarization

KW - Humans

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Peptides/chemistry

KW - Protein Binding

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors

KW - Substrate Specificity

KW - src-Family Kinases/antagonists & inhibitors

U2 - 10.1021/cb400903u

DO - 10.1021/cb400903u

M3 - SCORING: Journal article

C2 - 24387659

VL - 9

SP - 769

EP - 776

JO - ACS CHEM BIOL

JF - ACS CHEM BIOL

SN - 1554-8929

IS - 3

ER -