7PVU

Crystal structure of p38alpha C162S in complex with CAS2094511-69-8, P 1 21 1

Summary for 7PVU

• Entry DOI: 10.2210/pdb7pvu/pdb
• Related: 7PV3 7Q1A
• Descriptor: Mitogen-activated protein kinase 14, N-(2-cyclobutyl-1H-1,3-benzodiazol-5-yl)-2-fluorobenzene-1-sulfonamide (3 entities in total)
• Functional Keywords: kinase, enzyme, inhibitor, ligand, oncoprotein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 82815.43

Authors

Baginski, B.,Pous, J.,Gonzalez, L.,Macias, M.J.,Nebreda, A.R. (deposition date: 2021-10-05, release date: 2023-05-17, Last modification date: 2024-02-07)

Primary citation

Gonzalez, L.,Diaz, L.,Pous, J.,Baginski, B.,Duran-Corbera, A.,Scarpa, M.,Brun-Heath, I.,Igea, A.,Martin-Malpartida, P.,Ruiz, L.,Pallara, C.,Esguerra, M.,Colizzi, F.,Mayor-Ruiz, C.,Biondi, R.M.,Soliva, R.,Macias, M.J.,Orozco, M.,Nebreda, A.R.
Characterization of p38 alpha autophosphorylation inhibitors that target the non-canonical activation pathway.
Nat Commun, 14:3318-3318, 2023

PubMed Abstract: p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.

PubMed: 37308482
DOI: 10.1038/s41467-023-39051-x

Experimental method

X-RAY DIFFRACTION (2.154 Å)