5CGI

Yeast 20S proteasome beta5-G48C mutant in complex with ONX 0914

Summary for 5CGI

• Entry DOI: 10.2210/pdb5cgi/pdb
• Related: 1RYP
• Related PRD ID: PRD_000991
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (20 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, proteasome, mutant, inhibitor, binding analysis, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 28
• Total formula weight: 735743.45

Authors

Dubiella, C.,Groll, M. (deposition date: 2015-07-09, release date: 2015-11-25, Last modification date: 2024-10-23)

Primary citation

Dubiella, C.,Baur, R.,Cui, H.,Huber, E.M.,Groll, M.
Selective Inhibition of the Immunoproteasome by Structure-Based Targeting of a Non-catalytic Cysteine.
Angew.Chem.Int.Ed.Engl., 54:15888-15891, 2015

PubMed Abstract: Clinically applied proteasome inhibitors induce cell death by concomitant blockage of constitutive and immunoproteasomes. In contrast, selective immunoproteasome inhibition is less cytotoxic and has the potential to modulate chronic inflammation and autoimmune diseases. In this study, we rationally designed decarboxylated peptides that covalently target a non-catalytic cysteine of the immunoproteasome subunit β5i with α-chloroacetamide-containing sidechains. The enhanced isoform specificity decreased cytotoxic effects and the compound suppressed the production of inflammatory cytokines. Structure-based optimization led to over 150-fold selectivity for subunit β5i over β5c. This new compound class provides a promising starting point for the development of selective immunoproteasome inhibitors as potential anti-inflammatory agents.

PubMed: 26563572
DOI: 10.1002/anie.201506631

Experimental method

X-RAY DIFFRACTION (2.8 Å)