4FZC

20S yeast proteasome in complex with cepafungin I

Summary for 4FZC

• Entry DOI: 10.2210/pdb4fzc/pdb
• Related: 1RYP 2ZCY
• Related PRD ID: PRD_001018
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: ubiquitin, proteasome, drug development, inhibitor, natural product, n-terminal nucleophilic hydrolase, protein degradation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Total number of polymer chains: 32
• Total formula weight: 706425.12

Authors

Stein, M.,Beck, P.,Kaiser, M.,Dudler, R.,Becker, C.F.W.,Groll, M. (deposition date: 2012-07-06, release date: 2012-10-24, Last modification date: 2023-11-15)

Primary citation

Stein, M.L.,Beck, P.,Kaiser, M.,Dudler, R.,Becker, C.F.,Groll, M.
One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor.
Proc.Natl.Acad.Sci.USA, 109:18367-18371, 2012

PubMed Abstract: Natural products represent valuable lead structures for drug discovery. However, for most bioactive compounds no cellular target is yet identified and many substances predicted from genome analysis are inaccessible due to their life stage-dependent biosynthesis, which is not reflected in common isolation procedures. In response to these issues, an NMR-based and target-directed protease assay for inhibitor detection of the proteasome was developed. The methodology is suitable for one-shot identification of inhibitors in conglomerates and crude culture broths. The technique was applied for analysis of the different life stages of the bacterium Photorhabdus luminescens, which resulted in the isolation and characterization of cepafungin I (CepI), the strongest proteasome inhibitor described to date. Its biosynthesis is strictly regulated and solely induced by the specific environmental conditions determined by our methodology. The transferability of the developed technique to other drug targets may disclose an abundance of novel compounds applicable for drug development.

PubMed: 23091006
DOI: 10.1073/pnas.1211423109

Experimental method

X-RAY DIFFRACTION (2.8 Å)