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PDBsum entry 4qv6
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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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Bortezomib-Resistant mutant proteasomes: structural and biochemical evaluation with carfilzomib and onx 0914.
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Authors
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E.M.Huber,
W.Heinemeyer,
M.Groll.
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Ref.
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Structure, 2015,
23,
407-417.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of the 20S proteasome by bortezomib (Velcade) constitutes a
successfully applied therapy for blood cancer. However, emerging resistance
restricts its medicinal use. For example, mutations in the proteolytically
active β5-subunit of the proteasome, the main target of inhibitors, were
reported to impair drug binding and thus to reduce therapeutic efficacy. Using
yeast as a model system, we describe here a systematic evaluation of these
mutations by cell growth analysis, proteasome inhibition assays, and X-ray
crystallography. The 11 mutants examined display decreased proliferation rates,
impaired proteolytic activity, and marked resistance to bortezomib as well as
the α',β'-epoxyketone inhibitors carfilzomib (Kyprolis) and ONX 0914, while
the second-generation compound carfilzomib was the least affected. In total, 49
proteasome X-ray structures, including structural data on proteasome-carfilzomib
complexes, reveal three distinct molecular mechanisms that hamper both drug
binding and natural substrate turnover to an extent that is still compatible
with cell survival.
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