2gpl
From Proteopedia
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[[Image:2gpl.gif|left|200px]] | [[Image:2gpl.gif|left|200px]] | ||
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'''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors''' | '''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors''' | ||
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[[Category: Moroder, M.]] | [[Category: Moroder, M.]] | ||
[[Category: Weyher, E.]] | [[Category: Weyher, E.]] | ||
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Revision as of 02:22, 4 May 2008
TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors
Overview
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.
About this Structure
2GPL is a Protein complex structure of sequences from Saccharomyces cerevisiae. Full crystallographic information is available from OCA.
Reference
TMC-95-based inhibitor design provides evidence for the catalytic versatility of the proteasome., Groll M, Gotz M, Kaiser M, Weyher E, Moroder L, Chem Biol. 2006 Jun;13(6):607-14. PMID:16793518 Page seeded by OCA on Sun May 4 05:22:24 2008
