Groll, Michael; Götz, Marion; Kaiser, Markus; Weyher, Elisabeth; Moroder, Luis:
TMC-95-Based Inhibitor Design Provides Evidence for the Catalytic Versatility of the Proteasome
In: Chemistry and Biology, Jg. 13 (2006), Heft 6, S. 607 - 614
2006Artikel/Aufsatz in Zeitschrift
Biologie
Damit verbunden: 1 Publikation(en)
Titel:
TMC-95-Based Inhibitor Design Provides Evidence for the Catalytic Versatility of the Proteasome
Autor*in:
Groll, Michael;Götz, Marion;Kaiser, MarkusUDE
LSF ID
52590
ORCID
0000-0002-6540-8520ORCID iD
Sonstiges
der Hochschule zugeordnete*r Autor*in
;
Weyher, Elisabeth;Moroder, Luis
Erscheinungsjahr:
2006

Abstract:

TMC-95's natural cyclic tripeptide metabolites represent potent competitive proteasome inhibitors. The constrained conformation of TMC-95 proteasomal inhibitors provides the driving force for entropically high-affinity binding. Based on the crystal structure of the proteasome:TMC-95A complex, the synthetically challenging TMC-95 core structure was used for the design and synthesis of less demanding biphenyl-ether macrocycles, in which the biphenyl-ether moiety functions as an endocyclic clamp restricting its tripeptide backbone. These simplified analogs allowed us to identify high plasticity of the proteasomal tryptic-like specificity pocket. Biphenyl-ether compounds extended with an amide group were hydrolyzed by the proteasome, although the crystal structure of such proteasome:biphenyl-ether complexes revealed quenching of proteolysis at the acyl-enzyme intermediate. Our data reveal that biphenyl-ether derivatives bind noncovalently to the proteasomal tryptic-like active site in a reversible substrate-like manner without allosteric changes of active site residues.