The p38a protein, an important enzyme involved in the regulation of a wide range of cellular functions, is thought to play a significant role in various diseases such as cancer, chronic inflammation and neurodegenerative disorders. Since its identification, numerous pharmaceutical companies and research groups have invested significant resources in the development of inhibitors targeting this protein. Despite these efforts, the results have not yet reached the expected level required for successful drug development.

ICREA researchers at IRB Barcelona, ​​Dr. Maria Macias and Dr. A research team led by Ángel R. Nebreda discovered that p38α adopts a previously unidentified conformation. In short, they discovered a new “oxidized” form in which a disulfide bridge was built. The protein temporarily assumes this form depending on the redox state of the cell. This new form of p38a is described in the journal Nature Communication it does not allow binding to activators or substrates and therefore cannot perform its characteristic functions. However, this process is reversible and protein function is restored under reparative conditions.

“The identification of a new form of p38α may explain previous difficulties in developing effective p38α inhibitors, as research has so far focused on reduced conformations. Our results open new avenues for the development of therapeutic compounds that more precisely modulate p38α activity,” explains the ICREA researcher and Dr. D., head of the Laboratory for Structural Characterization of Macromolecular Aggregates at IRB Barcelona. Macias.

Oxidized form and reduced form

The Protein Data Bank contains 357 structures of the p38α protein, but all of them correspond to its reconstructed form, which is the only form known so far. The predominance of this form may be related to the predominance of experimental conditions involving reducing agents in structural studies. In the oxidized form described in this study, a disulfide bridge is established, forcing conformational changes and blocking access to the binding site of activators and substrates. Thus, this is a novel inactive form of p38α that will be present under certain cellular conditions.

“Studying kinases in their oxidized forms is difficult due to the influence of oxidative stress conditions and the transient nature of these forms in the cellular environment,” explained Dr. The first authors of the study are Joan Pous and Pau Martin Malpartida and PhD student Blazej Baginski. “But the key to effective pharmacological solutions may lie in these forms,” they concluded.

A promising approach

This new form demonstrates the mechanism of action of p38α, which is regulated by the redox state of the cell, thus explaining the biochemical observations described to date, but does not have a structural molecular basis. In future studies, researchers will focus on examining new interaction gaps that arise in the oxidized form, as they could help inactivate the protein without interfering with the catalytic center, thereby achieving specificity.