Pioneering Discovery: IRB Barcelona Team Unveils New Form of p38a Protein, Revolutionizing Drug Development

In a groundbreaking study that could revolutionize therapeutic approaches for several diseases, researchers from IRB Barcelona have made a significant discovery involving the p38a protein. The team, led by ICREA researchers Dr. Maria Macias and Dr. Angel R. Nebreda, revealed an "oxidized" form of the protein, a finding that has immense implications for the treatment of cancer, chronic inflammation, and neurodegenerative disorders. This study, published in Nature Communications on November 31, 2023, overturns previous understandings of the protein's behavior and offers new avenues for drug development.

Despite considerable efforts by numerous pharmaceutical companies to create inhibitors targeting p38a, success has been limited. The IRB Barcelona team's revelation of this new protein conformation, characterized by a unique disulfide bridge, could explain these past challenges. This oxidized form, which temporarily emerges depending on the cell's redox state, disrupts the binding with activators or substrates, rendering the protein inactive. However, this transformation is reversible, and normal function resumes under reducing conditions.

The discovery is a result of detailed structural analysis. Of the 357 structures of p38a protein recorded in the Protein Data Bank, all were of its reduced form. The oxidized form, newly described in this study, presents a previously unknown inactive state of p38a that occurs under specific cellular conditions.

Joan Pous, Pau Martin Malpartida, and doctoral student Blazej Baginski, the first authors of the study, emphasize the complexity of studying kinases in oxidized forms due to oxidative stress and their transient nature. This discovery not only provides a structural basis for biochemical observations but also suggests new pharmacological strategies targeting these oxidized forms.

The research, developed in collaboration with Dr. Modesto Orozco’s laboratory at IRB Barcelona and the University of Barcelona, and Nostrum Biodiscovery, was funded by various prestigious bodies including MICINN, ERC, AGAUR, and the BBVA Foundation. The team's future work will focus on exploring new interaction cavities in the oxidized form, which may enable the inactivation of the protein without interfering with the catalytic center, thereby increasing specificity in drug design.

This landmark discovery opens up a promising new chapter in the fight against diseases associated with p38a, offering hope for more effective treatments through a deeper understanding of the protein's behavior under varying cellular conditions.