2023-12-19 15:10:27
A scientific team of ICREA researchers from IRB Barcelona, has discovered that the p38a protein adopts a conformation not previously described. Specifically, researchers have discovered a new “oxidized” form, which the protein would adopt temporarily depending on the redox state of the cell, in which a disulfide bridge is established.
This new form of p38a, which has been described in the journal ‘Nature Communications‘, does not allow binding with activators or substrates, so it is not capable of performing the characteristic functions of this kinase. This is a reversible process, and protein function is recovered under reducing conditions.
Since its discovery, various pharmaceutical companies and numerous research groups have dedicated considerable efforts to the development of molecules aimed at inhibiting this protein, however, the results have not met expectations for the development of drugs.
‘The identification of a new form of p38a could explain previous difficulties in designing effective p38a inhibitors, since until now studies have focused on reduced conformations. Our results open new avenues for the development of therapeutic compounds that modulate the activity of p38a more precisely,” explains Maria Macias, ICREA researcher.
So far there are 357 structures of the p38a protein published in the database of Protein Data Bank, but all correspond to its reduced form, the only one known so far. This is possibly due to the prevalence of experimental conditions that include the presence of reducing agents in the structural studies carried out.
«The study of kinases in their oxidized form is complex due to the influence of oxidative stress conditions and the transitory nature of these forms in the cellular environment.», explain the authors of the work. “However, the key to addressing them effectively from a pharmacological point of view may lie in them,” they conclude.
A promising approach
This new form illustrates a mechanism of action of p38a regulated by the cellular redox state, explaining biochemical observations described so far but without a structural molecular basis.
In future work, the researchers will focus on exploring new interaction cavities that appear in the oxidized form, since they can help inactivate the protein without intervening in the catalytic center, thus gaining specificity.
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