3DY4

Structural analysis of spiro beta-lactone proteasome inhibitors.

(2008) J Am Chem Soc 130: 14981-14983

• PubMed: 18928262 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/ja806059t
• Primary Citation of Related Structures:  
  3DY3, 3DY4


• PubMed Abstract: 
  

  Spiro beta-lactone-based proteasome inhibitors were discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin (1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two analogues covalently bound to the 20S proteasome permitted characterization of the important stabilizing interactions between each inhibitor and the proteasome's key catalytic N-terminal threonine residue. This structural data support the hypothesis that the discrepancy in potency between 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.

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Organizational Affiliation: 

Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.