2gpl | pdb_00002gpl
TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors
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| 2gpl, resolution 2.81Å | |||||||||||||
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| Ligands: | BIQ | ||||||||||||
| Gene: | PRS4, PRE8 (Saccharomyces cerevisiae), PRE1 (Saccharomyces cerevisiae), PRE2, DOA3, PRG1 (Saccharomyces cerevisiae), PRS3, PRE7, PTS1 (Saccharomyces cerevisiae), PRE4 (Saccharomyces cerevisiae), PRE3 (Saccharomyces cerevisiae), PRS5, PRE9 (Saccharomyces cerevisiae), PRE6 (Saccharomyces cerevisiae), PUP2, DOA5 (Saccharomyces cerevisiae), PRE5 (Saccharomyces cerevisiae), PRS1, PRC1, PRE10 (Saccharomyces cerevisiae), PRS2, PRC2, SCL1 (Saccharomyces cerevisiae), PUP1 (Saccharomyces cerevisiae), PUP3 (Saccharomyces cerevisiae) | ||||||||||||
| Activity: | Proteasome endopeptidase complex, with EC number 3.4.25.1 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
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
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