Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α

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 ()
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Joan Pous: The Barcelona Institute of Science and Technology
Blazej Baginski: The Barcelona Institute of Science and Technology
Pau Martin-Malpartida: The Barcelona Institute of Science and Technology
Lorena González: The Barcelona Institute of Science and Technology
Margherita Scarpa: The Barcelona Institute of Science and Technology
Eric Aragon: The Barcelona Institute of Science and Technology
Lidia Ruiz: The Barcelona Institute of Science and Technology
Rebeca A. Mees: The Barcelona Institute of Science and Technology
Javier Iglesias-Fernández: Nostrum Biodiscovery
Modesto Orozco: The Barcelona Institute of Science and Technology
Angel R. Nebreda: The Barcelona Institute of Science and Technology
Maria J. Macias: The Barcelona Institute of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Many functional aspects of the protein kinase p38α have been illustrated by more than three hundred structures determined in the presence of reducing agents. These structures correspond to free forms and complexes with activators, substrates, and inhibitors. Here we report the conformation of an oxidized state with an intramolecular disulfide bond between Cys119 and Cys162 that is conserved in vertebrates. The structure of the oxidized state does not affect the conformation of the catalytic site, but alters the docking groove by partially unwinding and displacing the short αD helix due to the movement of Cys119 towards Cys162. The transition between oxidized and reduced conformations provides a mechanism for fine-tuning p38α activity as a function of redox conditions, beyond its activation loop phosphorylation. Moreover, the conformational equilibrium between these redox forms reveals an unexplored cleft for p38α inhibitor design that we describe in detail.

Date: 2023
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DOI: 10.1038/s41467-023-43763-5

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