4Z1L

Yeast 20S proteasome in complex with belactosin C derivative 3

Summary for 4Z1L

• Entry DOI: 10.2210/pdb4z1l/pdb
• Related: 1RYP 3E47
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 entities in total)
• Functional Keywords: hydrolase, proteasome, inhibitor, binding analysis, lead structure motif, 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: 733423.33

Authors

Huber, E.M.,Groll, M. (deposition date: 2015-03-27, release date: 2015-05-27, Last modification date: 2024-10-09)

Primary citation

Groll, M.,Korotkov, V.S.,Huber, E.M.,de Meijere, A.,Ludwig, A.
A Minimal beta-Lactone Fragment for Selective beta 5c or beta 5i Proteasome Inhibitors.
Angew.Chem.Int.Ed.Engl., 54:7810-7814, 2015

PubMed Abstract: Broad-spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β-lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo-isoleucin) or an isopropyl (pseudo-valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC50=14 nM) than the valine counterpart. Cell culture experiments demonstrate the cell-permeability of the compounds and X-ray crystallography data highlight them as minimal fragments that occupy primed and non-primed pockets of the active sites of the proteasome. Together, these results qualify β-lactones as a promising lead-structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.

PubMed: 25973989
DOI: 10.1002/anie.201502931

Experimental method

X-RAY DIFFRACTION (3 Å)