Our outcomes open up new opportunities for the advancement of therapeutic substances that modulate the activity of p38a more specifically,” describes Dr. Macías, ICREA researcher and head of the Structural Characterization of Macromolecular Assemblies laboratory at IRB Barcelona.An oxidized kind and a reduced formThe Protein Data Bank holds 357 structures of p38a protein, but they all correspond to its reduced type– the only one understood so far.”The research study of kinases in their oxidized types is complex due to the influence of oxidative tension conditions and the transience of these forms in the cellular environment,” explained Drs. Joan Pous and Pau Martin Malpartida and doctoral trainee Blazej Baginski, first authors of the research study. “However, the key to addressing them efficiently from a pharmacological perspective might lie in these kinds,” they conclude.An appealing approachThis new kind highlights a mechanism of action of p38a controlled by the cellular redox state, therefore describing biochemical observations described to date however with no structural molecular basis.In future work, the scientists will focus on checking out new interaction cavities that appear in the oxidized type as these may help to suspend the protein without interfering with the catalytic center, therefore gaining specificity.Reference: “Structural basis of a redox-dependent conformational switch that manages the stress kinase p38α” by Joan Pous, Blazej Baginski, Pau Martin-Malpartida, Lorena González, Margherita Scarpa, Eric Aragon, Lidia Ruiz, Rebeca A. Mees, Javier Iglesias-Fernández, Modesto Orozco, Angel R. Nebreda and Maria J. Macias, 31 November 2023, Nature Communications.DOI: 10.1038/ s41467-023-43763-5The work was established in collaboration with Dr. Modesto Orozcos laboratory at IRB Barcelona and the University of Barcelona, and Nostrum Biodiscovery.
Our results open up brand-new opportunities for the development of healing compounds that regulate the activity of p38a more exactly,” describes Dr. Macías, ICREA researcher and head of the Structural Characterization of Macromolecular Assemblies lab at IRB Barcelona.An oxidized kind and a lowered formThe Protein Data Bank holds 357 structures of p38a protein, but they all correspond to its reduced kind– the just one understood so far.”The study of kinases in their oxidized kinds is complex due to the influence of oxidative tension conditions and the transience of these forms in the cellular environment,” explained Drs. Joan Pous and Pau Martin Malpartida and doctoral student Blazej Baginski, first authors of the research study. “However, the secret to resolving them effectively from a medicinal perspective might lie in these types,” they conclude.A promising approachThis brand-new type highlights a mechanism of action of p38a regulated by the cellular redox state, consequently describing biochemical observations explained to date however with no structural molecular basis.In future work, the researchers will focus on exploring brand-new interaction cavities that appear in the oxidized kind as these may assist to suspend the protein without interfering with the catalytic center, therefore getting specificity.Reference: “Structural basis of a redox-dependent conformational switch that regulates the tension kinase p38α” by Joan Pous, Blazej Baginski, Pau Martin-Malpartida, Lorena González, Margherita Scarpa, Eric Aragon, Lidia Ruiz, Rebeca A. Mees, Javier Iglesias-Fernández, Modesto Orozco, Angel R. Nebreda and Maria J. Macias, 31 November 2023, Nature Communications.DOI: 10.1038/ s41467-023-43763-5The work was established in collaboration with Dr. Modesto Orozcos lab at IRB Barcelona and the University of Barcelona, and Nostrum Biodiscovery.
