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Indolo-Phakellins as [beta]5-Specific Noncovalent Proteasome Inhibitors
Ist Teil von
Angewandte Chemie International Edition, 2015-02, Vol.54 (9), p.2830
Auflage
International ed. in English
Ort / Verlag
Weinheim: Wiley Subscription Services, Inc
Erscheinungsjahr
2015
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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 S3subpocket of the proteasomal [beta]5 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.
Sprache
Englisch
Identifikatoren
ISSN: 1433-7851
eISSN: 1521-3773
DOI: 10.1002/anie.201410168
Titel-ID: cdi_proquest_journals_1655509188
Format
–
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