AI Article Synopsis
- - The study focuses on p90 ribosomal S6 kinases (RSKs), which have two kinase domains, NTKD and CTKD, with CTKD activation primarily regulated by ERK1/2 phosphorylation and an autoinhibitory structure.
- - Researchers conducted mutations on RSK CTKDs to better understand the mechanism of autoinhibition and designed variants that activate without ERK phosphorylation, such as RSK2 T577E D694*.
- - The new constructs allow for the measurement of the inhibitory effects of ATP-competitive inhibitors and help establish methods for determining the specificity of covalent CTKD inhibitors.
Article Abstract
The p90 ribosomal S6 kinases (RSKs) contain two distinct catalytic kinase domains, the N-terminal and C-terminal kinase domains (NTKD and CTKD, respectively). The activation of CTKD is regulated by phosphorylation by extracellular signal-regulated kinase (ERK1/2) and an autoinhibitory αL helix. Through a mutational series in vitro of the RSK CTKDs, we found a complex mechanism lifting autoinhibition that led us to design constitutively active RSK CTKDs. These are based on a phosphomimetic mutation and a C-terminal truncation (e.g., RSK2 T577E D694*) where a high activity in absence of ERK phosphorylation is obtained. Using these constructs, we characterize IC values of ATP-competitive inhibitors and provide a setup for determining specificity constants (k/K) of covalent CTKD inhibitors.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941302 | PMC |
| http://dx.doi.org/10.26508/lsa.202201425 | DOI Listing |
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