New peptide-based pharmacophore activates 20S proteasome
Paweł A. Osmulski , Przemysław Karpowicz , Elżbieta Jankowska , Jonathan Bohmann , Andrew M. Pickering , Maria Gaczyńska
AbstractThe proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use.
|Journal series||Molecules, ISSN 1420-3049, (N/A 100 pkt)|
|Publication size in sheets||0.8|
|Keywords in English||proteasome, activation, allostery, peptides, beta turn, proteasome dynamics, atomic force microscopy|
|License||Repository; published final; ; with publication|
|Score||= 100.0, 24-03-2020, ArticleFromJournal|
|Publication indicators||: 2017 = 1.146; : 2018 = 3.06 (2) - 2018=3.38 (5)|
|Licencja||Utwór jest udostępniany na licencji Creative Commons Uznanie autorstwa 4.0 Międzynarodowe (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/|
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