Constant exposure of cells to stressing agents, such as pathogens, may disturb an organism's normal functioning. To fight stress, cells have developed several coping mechanisms, including the inflammatory response.
. They have obtained the first structure of p38α being activated by another regulatory protein kinase—MKK6—opening up new directions to develop drugs to stop cytokine storms.Matthew Bowler, a researcher at EMBL Grenoble, has been studying kinases for more than a decade. This group of enzymes plays an important role in regulating complex processes in the cell by acting as a 'switch' to transmit signals and activate gene expression.
Because the kinase chain reaction can come from different 'branches' of the logic circuit, this last switch is a particularly relevant drug target. The inflammatory response is regulated by p38α and is highly activated during a cytokine storm. Inactivating it could prevent inflammation from occurring, instead of trying to treat it while it is already underway.
Without this essential information about how the activation is triggered, drugs have mostly targeted the kinases' nucleotide-binding site—a common and well-known pocket present in all kinases, where the phosphate transfer occurs. The lack of drug specificity due to a common binding site across kinases means that a drug designed to stop one kinase from signaling could also stop others.
They were hampered by the fact that the interactions of the MKK6-p38α complex cannot be determined by macromolecular crystallography, a structural biology technique often employed to investigate proteins but that is particularly challenging to apply in the case of such dynamic proteins., particularly during the last decade, raised new hopes. In 2016, Bowler and new Ph.D.
"This could be an interesting target for inhibitors that block this specific interaction, and consequently the signal triggering the inflammatory response," explained Juyoux.molecular dynamics simulations Crucially, by comparing these simulations with the SAXS data they were able to model how the two proteins interact prior to catalysis."The beauty of combining the state-of-the-art simulations with SAXS and cryo-EM data through advanced statistical approaches is that we can 'see' the dance of the two kinases approaching one another, while knowing that what we see in the computer is fully supported by all the experimental data available," explained Francesco Gervasio.
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