4INT

Yeast 20S proteasome in complex with the vinyl sulfone LU122

Summary for 4INT

• Entry DOI: 10.2210/pdb4int/pdb
• Related: 1RYP 4INR 4INU
• Related PRD ID: PRD_000992
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: ups, drug discovery, irreversible inhibition, ntn hydrolase, non-lysosomal protein breakdown, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 730846.80

Authors

Geurink, P.P.,van der Linden, W.A.,Mirabella, A.C.,Gallastegui, N.,de Bruin, G.,Blom, A.E.M.,Voges, M.J.,Mock, E.D.,Florea, B.I.,van der Marel, G.A.,Driessen, C.,van der Stelt, M.,Groll, M.,Overkleeft, H.S.,Kisselev, A.F. (deposition date: 2013-01-06, release date: 2013-01-30, Last modification date: 2024-10-16)

Primary citation

Geurink, P.P.,van der Linden, W.A.,Mirabella, A.C.,Gallastegui, N.,de Bruin, G.,Blom, A.E.,Voges, M.J.,Mock, E.D.,Florea, B.I.,van der Marel, G.A.,Driessen, C.,van der Stelt, M.,Groll, M.,Overkleeft, H.S.,Kisselev, A.F.
Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites.
J.Med.Chem., 56:1262-1275, 2013

PubMed Abstract: Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that combinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antineoplastic activity than combinations currently used clinically.

PubMed: 23320547
DOI: 10.1021/jm3016987

Experimental method

X-RAY DIFFRACTION (2.9 Å)