4NO8

yCP in complex with Z-Leu-Leu-Leu-ketoamide

Summary for 4NO8

• Entry DOI: 10.2210/pdb4no8/pdb
• Related: 1RYP 4NNN 4NNW 4NO1 4NO6 4NO9
• Related PRD ID: PRD_001205
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (17 entities in total)
• Functional Keywords: proteasome, peptide electrophile, binding analysis, reversible inhibitor, ketoamide, 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: 732438.72

Authors

Stein, M.L.,Cui, H.,Beck, P.,Dubiella, C.,Voss, C.,Krueger, A.,Schmidt, B.,Groll, M. (deposition date: 2013-11-19, release date: 2014-02-12, Last modification date: 2024-10-16)

Primary citation

Stein, M.L.,Cui, H.,Beck, P.,Dubiella, C.,Voss, C.,Kruger, A.,Schmidt, B.,Groll, M.
Systematic Comparison of Peptidic Proteasome Inhibitors Highlights the alpha-Ketoamide Electrophile as an Auspicious Reversible Lead Motif.
Angew.Chem.Int.Ed.Engl., 53:1679-1683, 2014

PubMed Abstract: The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophilic C-terminus by which they react with the active proteolytic sites. Although the peptide moiety has attracted much attention in terms of subunit selectivity, the target specificity and biological stability of the compounds are largely determined by the reactive warheads. In this study, we have carried out a systematic investigation of described electrophiles by a combination of in vitro, in vivo, and structural methods in order to disclose the implications of altered functionality and chemical reactivity. Thereby, we were able to introduce and characterize the class of α-ketoamides as the most potent reversible inhibitors with possible applications for the therapy of solid tumors as well as autoimmune disorders.

PubMed: 24403024
DOI: 10.1002/anie.201308984

Experimental method

X-RAY DIFFRACTION (2.7 Å)