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A novel GSK-3 inhibitor binds to GSK-3β via a reversible, time and Cys-199-dependent mechanism.
- Source :
-
Bioorganic & Medicinal Chemistry . Jun2021, Vol. 40, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
-
Abstract
- [Display omitted] Glycogen synthase kinase-3 (GSK-3) has been implicated in numerous pathologies making GSK-3 an attractive therapeutic target. Our group has identified a compound termed COB-187 that is a potent and selective inhibitor of GSK-3. In this study, we probed the mechanism by which COB-187 inhibits GSK-3β. Progress curves, generated via real-time monitoring of kinase activity, indicated that COB-187 inhibition of GSK-3β is time-dependent and subsequent jump dilution assays revealed that COB-187 binding to GSK-3β is reversible. Further, a plot of the kinetic constant (k obs) versus COB-187 concentration suggested that, within the range of concentrations studied, COB-187 binds to GSK-3β via an induced-fit mechanism. There is a critical cysteine residue at the entry to the active site of GSK-3β (Cys-199). We generated a mutant version of GSK-3β wherein Cys-199 was substituted with an alanine. This mutation caused a dramatic decrease in the activity of COB-187; specifically, an IC 50 in the nM range for wild type versus >100 µM for the mutant. A screen of COB-187 against 34 kinases that contain a conserved cysteine in their active site revealed that COB-187 is highly selective for GSK-3 indicating that COB-187′s inhibition of GSK-3β via Cys-199 is specific. Combined, these findings suggest that COB-187 inhibits GSK-3β via a specific, reversible, time and Cys-199-dependent mechanism. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 40
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 150521871
- Full Text :
- https://doi.org/10.1016/j.bmc.2021.116179