4R17

Ligand-induced aziridine-formation at subunit beta5 of the yeast 20S proteasome

Summary for 4R17

• Entry DOI: 10.2210/pdb4r17/pdb
• Related: 1RYP 4R18
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (17 entities in total)
• Functional Keywords: proteasome, drug development, binding analysis, umpolung, crosslink, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae S288c (Baker's yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 28
• Total formula weight: 731520.33

Authors

Dubiella, C.,Cui, H.,Gersch, M.,Brouwer, A.J.,Sieber, S.A.,Krueger, A.,Liskamp, R.,Groll, M. (deposition date: 2014-08-04, release date: 2014-10-15, Last modification date: 2023-09-20)

Primary citation

Dubiella, C.,Cui, H.,Gersch, M.,Brouwer, A.J.,Sieber, S.A.,Kruger, A.,Liskamp, R.M.,Groll, M.
Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site.
Angew.Chem.Int.Ed.Engl., 53:11969-11973, 2014

PubMed Abstract: The concept of proteasome inhibition ranks among the latest achievements in the treatment of blood cancer and represents a promising strategy for modulating autoimmune diseases. In this study, we describe peptidic sulfonyl fluoride inhibitors that selectively block the catalytic β5 subunit of the immunoproteasome by inducing only marginal cytotoxic effects. Structural and mass spectrometric analyses revealed a novel reaction mechanism involving polarity inversion and irreversible crosslinking of the proteasomal active site. We thus identified the sulfonyl fluoride headgroup for the development and optimization of immunoproteasome selective compounds and their possible application in autoimmune disorders.

PubMed: 25244435
DOI: 10.1002/anie.201406964

Experimental method

X-RAY DIFFRACTION (2.1 Å)