4JSU

Yeast 20S proteasome in complex with the dimerized linear mimetic of TMC-95A - yCP:3a

Summary for 4JSU

• Entry DOI: 10.2210/pdb4jsu/pdb
• Related: 1JD2 1RYP 4JSQ 4JT0
• Related PRD ID: PRD_001044
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (17 entities in total)
• Functional Keywords: ups, proteasome, drug discovery, non-covalent reversible inhibition, bivalence, tmc-95a derivatives, ntn hydrolase, non-lysosomal protein breakdown, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 32
• Total formula weight: 733287.75

Authors

Desvergne, A.,Genin, E.,Marechal, X.,Gallastegui, N.,Dufau, L.,Richy, N.,Groll, M.,Vidal, J.,Reboud-Ravaux, M. (deposition date: 2013-03-22, release date: 2013-05-01, Last modification date: 2023-11-15)

Primary citation

Desvergne, A.,Genin, E.,Marechal, X.,Gallastegui, N.,Dufau, L.,Richy, N.,Groll, M.,Vidal, J.,Reboud-Ravaux, M.
Dimerized linear mimics of a natural cyclopeptide (TMC-95A) are potent noncovalent inhibitors of the eukaryotic 20S proteasome
J.Med.Chem., 56:3367-3378, 2013

PubMed Abstract: Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously two of the six active sites of the eukaryotic 20S proteasome. The homodimerized compounds actively inhibited chymotrypsin-like (Ki = 6-11 nM) and trypsin-like activities, whereas postacid activity was poorly modified. The noncovalent binding mode was ascertained by X-ray crystallography of the inhibitors complexed with the yeast 20S proteasome. The inhibition of proteasomal activities in human cells was evaluated. The use of the multivalency inhibitor concept has produced highly efficient and selective noncovalent compounds (no inhibition of calpain and cathepsin) that have potential therapeutic advantages compared to covalent binders such as bortezomib and carfilzomib.

PubMed: 23540790
DOI: 10.1021/jm4002007

Experimental method

X-RAY DIFFRACTION (2.9 Å)