2GPL

TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors

Summary for 2GPL

• Entry DOI: 10.2210/pdb2gpl/pdb
• Related: 1JD2 1RYP
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices; ntn-hydrolase, hydrolase
• Biological source: Saccharomyces cerevisiae (baker's yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 28
• Total formula weight: 705527.59

Authors

Groll, M.,Goetz, M.,Kaiser, M.,Weyher, E.,Moroder, M. (deposition date: 2006-04-18, release date: 2006-07-11, Last modification date: 2023-08-30)

Primary citation

Groll, M.,Goetz, M.,Kaiser, M.,Weyher, E.,Moroder, L.
TMC-95-Based Inhibitor Design Provides Evidence for the Catalytic Versatility of the Proteasome.
Chem.Biol., 13:607-614, 2006

PubMed 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.

PubMed: 16793518
DOI: 10.1016/j.chembiol.2006.04.005

Experimental method

X-RAY DIFFRACTION (2.81 Å)