title: TMC-95-based inhibitor design provides evidence for the catalytic versatility of the proteasome.
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.
authors.affiliation: Ludwig-Maximilians-University, Department for Physiological Chemistry, Butenandtstrasse 5, Building B, D-81377 Munich, Germany. mgroll@med.uni-muenxhen.de
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Marion
authors.initials: M
authors.lastname: Götz
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weyher
authors.forename: Luis
authors.initials: L
authors.lastname: Moroder
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014357:Trypsin / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D003432:Cross-Linking Reagents; D010456:Peptides, Cyclic; D010647:Phenyl Ethers; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C408291:TMC-95A; D014361:Trypsin Inhibitors; D014357:Trypsin; D046988:Proteasome Endopeptidase Complex