3MG0

Structure of yeast 20S proteasome with bortezomib

Summary for 3MG0

• Entry DOI: 10.2210/pdb3mg0/pdb
• Related: 3MG4 3MG6 3MG7 3MG8
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: 20s proteasome, hydrolase
• Biological source: Saccharomyces cerevisiae (brewer's yeast,lager beer yeast,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: 706511.66

Authors

Sintchak, M.D. (deposition date: 2010-04-05, release date: 2011-05-18, Last modification date: 2023-09-06)

Primary citation

Blackburn, C.,Gigstad, K.M.,Hales, P.,Garcia, K.,Jones, M.,Bruzzese, F.J.,Barrett, C.,Liu, J.X.,Soucy, T.A.,Sappal, D.S.,Bump, N.,Olhava, E.J.,Fleming, P.,Dick, L.R.,Tsu, C.,Sintchak, M.D.,Blank, J.L.
Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit.
Biochem.J., 430:461-476, 2010

PubMed Abstract: The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.

PubMed: 20632995
DOI: 10.1042/BJ20100383

Experimental method

X-RAY DIFFRACTION (2.68 Å)