7PVU

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

7PVU の概要

• エントリーDOI: 10.2210/pdb7pvu/pdb
• 関連するPDBエントリー: 7PV3 7Q1A
• 分子名称: Mitogen-activated protein kinase 14, N-(2-cyclobutyl-1H-1,3-benzodiazol-5-yl)-2-fluorobenzene-1-sulfonamide (3 entities in total)
• 機能のキーワード: kinase, enzyme, inhibitor, ligand, oncoprotein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82815.43

構造登録者

Baginski, B.,Pous, J.,Gonzalez, L.,Macias, M.J.,Nebreda, A.R. (登録日: 2021-10-05, 公開日: 2023-05-17, 最終更新日: 2024-02-07)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.154 Å)