4RUR

Yeast 20S proteasome in complex with the alkaloid indolo-phakellin (4)

Summary for 4RUR

• Entry DOI: 10.2210/pdb4rur/pdb
• Related: 1RYP
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (17 entities in total)
• Functional Keywords: proteasome, alkaloid, reversible inhibition, drug discovery, halogen bonding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae S288c (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: 731989.93

Authors

Beck, P.,Lansdell, T.A.,Hewlett, N.M.,Tepe, J.J.,Groll, M. (deposition date: 2014-11-21, release date: 2014-12-10, Last modification date: 2023-09-20)

Primary citation

Beck, P.,Lansdell, T.A.,Hewlett, N.M.,Tepe, J.J.,Groll, M.
Indolo-Phakellins as beta 5-Specific Noncovalent Proteasome Inhibitors.
Angew.Chem.Int.Ed.Engl., 54:2830-2833, 2015

PubMed Abstract: The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug-like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo-phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure-based design of subunit-specific nonpeptidic proteasome-blockers.

PubMed: 25581903
DOI: 10.1002/anie.201410168

Experimental method

X-RAY DIFFRACTION (2.5 Å)