Redox‐Based Probes for Protein Tyrosine Phosphatases

Leonard, Stephen E.; García, Francisco J.; Goodsell, David S.; Carroll, Kate S.

doi:10.1002/ange.201007871

Cited by 9 publications

(9 citation statements)

References 51 publications

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“…Taking this one step further, whether this strategy could be exploited to selectively target EGFR in cancer cells with abnormally high concentrations of reactive oxygen species remains to be investigated. This approach need not be restricted to kinases, however, and could be applied to other enzymes or noncatalytic proteins with redox-sensitive cysteine residues, as we have demonstrated recently for PTPs 41 . These topics represent new and exciting avenues for future research.…”

Section: Discussionmentioning

confidence: 98%

Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity

et al. 2011

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Protein sulfenylation is a post-translational modification of emerging importance in higher eukaryotes. However, investigation of its diverse roles remains challenging, particularly within a native cellular environment. Herein we report the development and application of DYn-2, a new chemoselective probe for detecting sulfenylated proteins in human cells. These studies show that epidermal growth factor receptor–mediated signaling results in H2O2 production and oxidation of downstream proteins. In addition, we demonstrate that DYn-2 has the ability to detect differences in sulfenylation rates within the cell, which are associated with differences in target protein localization. We also show that the direct modification of epidermal growth factor receptor by H2O2 at a critical active site cysteine (Cys797) enhances its tyrosine kinase activity. Collectively, our findings reveal sulfenylation as a global signaling mechanism that is akin to phosphorylation and has regulatory implications for other receptor tyrosine kinases and irreversible inhibitors that target oxidant-sensitive cysteines in proteins.

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Section: Discussionmentioning

confidence: 98%

Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity

et al. 2011

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“…We have also used the Autodock suite as a tool for drug design and virtual screening against a number of targets, including HIV protease 12–14 , tuberculosis targets 15,16 , and beta-secretase 17,18 . AutoLigand was used to identify druggable sites for stabilizing a protein-protein interface 19 and covalent docking was used to explore covalent inhibitors of protein tyrosine phosphatases 20 .…”

Section: Applications Of the Protocolmentioning

confidence: 99%

Computational protein–ligand docking and virtual drug screening with the AutoDock suite

et al. 2016

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Computational docking can be used to predict bound conformations and free energies of binding for small molecule ligands to macromolecular targets. Docking is widely used for the study of biomolecular interactions and mechanisms, and is applied to structure-based drug design. The methods are fast enough to allow virtual screening of ligand libraries containing tens of thousands of compounds. This protocol covers the docking and virtual screening methods provided by the AutoDock suite of programs, including a basic docking of a drug molecule with an anticancer target, a virtual screen of this target with a small ligand library, docking with selective receptor flexibility, active site prediction, and docking with explicit hydration. The entire protocol will require approximately 5 hours.

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“…In addition, the dimedone scaffold (Figure 12) when incorporated into an appropriate binding module has also been demonstrated to exhibit selectivity for the sulfenic acid generated in PTP active site. 257 More recently, a novel immunochemical approach consisting of an antibody designed to recognize the conserved sequence of the PTP active site (VHCDMDSAG) harboring the catalytic cysteine modified with dimedone has been developed to directly profile oxidized PTPs. 258 It is anticipated that future work in this area will lead to novel therapeutic molecules that can covalently capture the oxidized forms of PTPs generated inside the cell under disease conditions.…”

Section: Therapeutic Targeting Of Ptp Regulatory Mechanismsmentioning

confidence: 99%

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Zhang

2017

Chem. Rev.

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Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic interventions. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination on a number of regulatory mechanisms including redox modulation, allosteric regulation, and protein oligomerization, in controlling PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.

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Redox‐Based Probes for Protein Tyrosine Phosphatases

Cited by 9 publications

References 51 publications

Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity

Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity

Computational protein–ligand docking and virtual drug screening with the AutoDock suite

Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

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