Download MendeleySelective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site.
Dubiella, C., Cui, H., Gersch, M., Brouwer, A.J., Sieber, S.A., Kruger, A., Liskamp, R.M., Groll, M.(2014) Angew Chem Int Ed Engl 53: 11969-11973
- PubMed: 25244435
- DOI: https://doi.org/10.1002/anie.201406964
- Primary Citation of Related Structures:
4R17, 4R18 - 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 ¦Â5 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.
Organizational Affiliation:
Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universit?t M¨¹nchen, Lichtenbergstrasse 4, 85747 Garching (Germany).
