2gpl
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TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors
OverviewOverview
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 StructureAbout this Structure
2GPL is a Protein complex structure of sequences from Saccharomyces cerevisiae with BIQ as ligand. Active as Proteasome endopeptidase complex, with EC number 3.4.25.1 Full crystallographic information is available from OCA.
ReferenceReference
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
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