scholarly journals Minimally disruptive optical control of protein tyrosine phosphatase 1B

2019 ◽  
Author(s):  
Akarawin Hongdusit ◽  
Peter H. Zwart ◽  
Banumathi Sankaran ◽  
Jerome M. Fox
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Regulatory Element ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Phosphatase 1B ◽  
Post Translational Modifications ◽  
Protein Tyrosine ◽  
Important Regulator ◽  
Obesity And Cancer

ABSTRACTProtein tyrosine phosphatases regulate a myriad of essential subcellular signaling events, yet they remain difficult to study in their native biophysical context. Here we develop a minimally disruptive optical approach to control protein tyrosine phosphatase 1B (PTP1B)—an important regulator of receptor tyrosine kinases and a therapeutic target for the treatment of diabetes, obesity, and cancer—and we use that approach to probe the intracellular function of this enzyme. Our conservative architecture for photocontrol, which consists of a protein-based light switch fused to an allosteric regulatory element, preserves the native structure, activity, and subcellular localization of PTP1B, affords changes in activity that match those elicited by post-translational modifications inside the cell, and permits experimental analyses of the molecular basis of optical modulation. Findings indicate, most strikingly, that small changes in the activity of PTP1B can cause large shifts in the phosphorylation states of its regulatory targets.

EXPERIMENTAL AND THEORETICAL STUDY OF THE MOVEMENT OF THE WPD FLEXIBLE LOOP OF HUMAN PROTEIN TYROSINE PHOSPHATASE PTP1B IN COMPLEX WITH HALIDE IONS

2012 ◽  
Vol 07 (03n04) ◽  
pp. 197-217
Author(s):  
ALINE KATZ ◽  
PATRICIA SAENZ-MÉNDEZ ◽  
ALEXANDRA COUSIDO-SIAH ◽  
ALBERTO D. PODJARNY ◽  
OSCAR N. VENTURA
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Enzymatic Catalysis ◽  
Protein Tyrosine Phosphatases ◽  
Md Simulations ◽  
Crystallographic Structure ◽  
Halide Ions ◽  
Post Translational Modification ◽  
Protein Tyrosine

Protein tyrosine phosphorylation is a post-translational modification mechanism, crucial for the regulation of nearly all aspects of cell life. This dynamic, reversible process is regulated by the balanced opposing activity of protein tyrosine kinases and protein tyrosine phosphatases. In particular, the protein tyrosine phosphatase 1B (PTP1B) is implicated in the regulation of the insulin-receptor activity, leptin-stimulated signal transduction pathways and other clinically relevant metabolic routes, and it has been found overexpressed or overregulated in human breasts, colon and ovary cancers. The WPD loop of the enzyme presents an inherent flexibility, and it plays a fundamental role in the enzymatic catalysis, turning it into a potential target in the design of new efficient PTP1B inhibitors. In order to determine the interactions that control the spatial conformation adopted by the WPD loop, complexes between the enzyme and halide ions ( Br- and I- in particular) were crystallized and their crystallographic structure determined, and the collective movements of the aforementioned complexes were studied through Molecular Dynamics (MD) simulations. Both studies yielded concordant results, indicating the existence of a relationship between the identity of the ion present in the complex and the strength of the interactions it establishes with the surrounding protein residues.

scholarly journals Toward selective inactivation of protein tyrosine phosphatase 1B via exo-affinity labeling agents

2014 ◽  
Author(s):  
◽  
Andrea Hicks Cummings
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Type Ii Diabetes ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Affinity Labeling ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Signaling ◽  
Protein Targets ◽  
Protein Tyrosine ◽  
Obesity And Cancer

Exo-affinity labeling agents are compounds that achieve selectivity by modifying non-catalytic residues in a protein. They have been utilized as tools in molecular biology and to make successful drugs for protein targets. Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target for type II diabetes, obesity and cancer. However, no compounds have been FDA approved for PTP1B due to selectivity and bioavailability issues with traditional compounds. We propose that exo-affinity labeling agents can be used to achieve selectivity in PTP1B. In this work we have designed, synthesized, and characterized the first exo-affinity for PTP1B. Using this work we can design better exo-affinity labeling agents that can be selective for PTP1B. This may have implications on drug design and general knowledge of protein signaling pathways.

scholarly journals Regulation of Phosphoinositide Levels in the Retina by Protein Tyrosine Phosphatase 1B and Growth Factor Receptor-Bound Protein 14

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 602
Author(s):  
Raju V. S. Rajala ◽  
Austin McCauley ◽  
Rahul Rajala ◽  
Kenneth Teel ◽  
Ammaji Rajala
Keyword(s):  
Growth Factor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Knockout Mouse ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Mouse Retina ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Growth Factor Receptor Bound

Protein tyrosine kinases and protein phosphatases play a critical role in cellular regulation. The length of a cellular response depends on the interplay between activating protein kinases and deactivating protein phosphatases. Protein tyrosine phosphatase 1B (PTP1B) and growth factor receptor-bound protein 14 (Grb14) are negative regulators of receptor tyrosine kinases. However, in the retina, we have previously shown that PTP1B inactivates insulin receptor signaling, whereas phosphorylated Grb14 inhibits PTP1B activity. In silico docking of phosphorylated Grb14 and PTP1B indicate critical residues in PTP1B that may mediate the interaction. Phosphoinositides (PIPs) are acidic lipids and minor constituents in the cell that play an important role in cellular processes. Their levels are regulated by growth factor signaling. Using phosphoinositide binding protein probes, we observed increased levels of PI(3)P, PI(4)P, PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3 in PTP1B knockout mouse retina and decreased levels of these PIPs in Grb14 knockout mouse retina. These observations suggest that the interplay between PTP1B and Grb14 can regulate PIP metabolism.

Inhibition of Protein Tyrosine Phosphatase 1B by Lutein Derivatives isolated from Mexican Oregano (Lippia graveolens)

2018 ◽  
Vol 17 (3) ◽  
pp. 134-139
Author(s):  
R.M. Perez-Gutierrez
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Spectroscopic Data ◽  
Methanol Extract ◽  
Tyrosine Phosphatase ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Value ◽  
Ic50 Values

Methanol extract from Lippia graveolens (Mexican oregano) was studied in order to identify inhibitory bioactives for protein tyrosine phosphatase 1B (PTP1B). Known flavone as lutein (1), and another flavone glycoside such as lutein-7-o-glucoside (2), 6-hydroxy-lutein-7-ohexoside (3) and lutein-7-o-ramnoide (4) were isolated from methanol extract of aerial parts of the Lippia graveolens. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR, MS and compared with spectroscopic data previously reported. These flavones were evaluated for PTP1B inhibitory activity. Among them, compounds 1 and 3 displayed potential inhibitory activity against PTP1B with IC50 values of 7.01 ± 1.25 μg/ml and 18.4 μg/ml, respectively. In addition, compound 2 and 4 showed moderate inhibitory activity with an IC50 value of 23.8 ± 6.21 and 67.8 ± 5.80 μg/ml respectively. Among the four compounds, luteolin was found to be the most potent PTP1B inhibitor compared to the positive control ursolic acid, with an IC50 value of 8.12 ± 1.06 μg/ml. These results indicate that flavonoids constituents contained in Lippia graveolens can be considered as a natural source for the treatment of type 2 diabetes.

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