Details

Autor(en) / Beteiligte

• Beck, Philipp
• Lansdell, Theresa A
• Hewlett, Nicole M
• Tepe, Jetze J
• Groll, Michael

Titel

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.