Proline- and Arginine-Rich Peptides as Flexible Allosteric Modulators of Human Proteasome Activity

Małgorzata Gizyńska, Julia Witkowska, Przemysław Karpowicz, Rafał Rostankowski, Estrella S. Chocron, Andrew M. Pickering, Pawel Osmulski, Maria Gaczynska, Elzbieta Jankowska

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Proline- and arginine-rich peptide PR11 is an allosteric inhibitor of 20S proteasome. We modified its sequence inter alia by introducing HbYX, RYX, or RHbX C-terminal extensions (Hb, hydrophobic moiety; R, arginine; Y, tyrosine; X, any residue). Consequently, we were able to improve inhibitory potency or to convert inhibitors into strong activators: the former with an aromatic penultimate Hb residue and the latter with the HbYX motif. The PR peptide activator stimulated 20S proteasome in vitro to efficiently degrade protein substrates, such as α-synuclein and enolase, but also activated proteasome in cultured fibroblasts. The positive and negative PR modulators differently influenced the proteasome conformational dynamics and affected opening of the substrate entry pore. The resolved crystal structure showed PR inhibitor bound far from the active sites, at the proteasome outer face, in the pocket used by natural activators. Our studies indicate the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold.

Original languageEnglish (US)
Pages (from-to)359-370
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine


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