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PDBsum entry 4no8
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Hydrolase/hydrolase inhibitor
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PDB id
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4no8
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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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222 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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Systematic comparison of peptidic proteasome inhibitors highlights the α-Ketoamide electrophile as an auspicious reversible lead motif.
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Authors
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M.L.Stein,
H.Cui,
P.Beck,
C.Dubiella,
C.Voss,
A.Krüger,
B.Schmidt,
M.Groll.
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Ref.
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Angew Chem Int Ed Engl, 2014,
53,
1679-1683.
[DOI no: ]
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PubMed id
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Abstract
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The ubiquitin-proteasome system (UPS) has been successfully targeted by both
academia and the pharmaceutical industry for oncological and immunological
applications. Typical proteasome inhibitors are based on a peptidic backbone
endowed with an electrophilic C-terminus by which they react with the active
proteolytic sites. Although the peptide moiety has attracted much attention in
terms of subunit selectivity, the target specificity and biological stability of
the compounds are largely determined by the reactive warheads. In this study, we
have carried out a systematic investigation of described electrophiles by a
combination of in vitro, in vivo, and structural methods in order to disclose
the implications of altered functionality and chemical reactivity. Thereby, we
were able to introduce and characterize the class of α-ketoamides as the most
potent reversible inhibitors with possible applications for the therapy of solid
tumors as well as autoimmune disorders.
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