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PDBsum entry 4rur
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Hydrolase/hydrolase inhibitor
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PDB id
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4rur
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Contents |
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250 a.a.
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244 a.a.
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240 a.a.
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235 a.a.
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231 a.a.
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243 a.a.
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241 a.a.
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226 a.a.
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204 a.a.
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195 a.a.
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212 a.a.
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222 a.a.
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233 a.a.
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196 a.a.
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References listed in PDB file
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Key reference
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Title
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Indolo-Phakellins as β5-Specific noncovalent proteasome inhibitors.
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Authors
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P.Beck,
T.A.Lansdell,
N.M.Hewlett,
J.J.Tepe,
M.Groll.
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Ref.
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Angew Chem Int Ed Engl, 2015,
54,
2830-2833.
[DOI no: ]
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PubMed id
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Abstract
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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.
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