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PDBsum entry 5m32
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Contents |
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230 a.a.
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234 a.a.
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234 a.a.
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233 a.a.
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234 a.a.
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232 a.a.
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233 a.a.
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221 a.a.
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204 a.a.
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196 a.a.
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200 a.a.
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213 a.a.
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216 a.a.
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202 a.a.
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347 a.a.
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333 a.a.
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361 a.a.
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348 a.a.
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363 a.a.
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332 a.a.
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230 a.a.
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155 a.a.
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364 a.a.
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415 a.a.
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375 a.a.
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206 a.a.
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75 a.a.
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101 a.a.
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259 a.a.
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26 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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Long-Range allosteric regulation of the human 26s proteasome by 20s proteasome-Targeting cancer drugs.
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Authors
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D.Haselbach,
J.Schrader,
F.Lambrecht,
F.Henneberg,
A.Chari,
H.Stark.
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Ref.
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Nat Commun, 2017,
8,
15578.
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PubMed id
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Abstract
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The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic
activity is essential for cellular homeostasis. Thus, it is an attractive target
for the development of chemotherapeutics. While the structural basis of core
particle (CP) inhibitors is largely understood, their structural impact on the
proteasome holoenzyme remains entirely elusive. Here, we determined the
structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug
binding modifies the energy landscape of conformational motion in the proteasome
regulatory particle (RP). Structurally, the energy barrier created by Oprozomib
triggers a long-range allosteric regulation, resulting in the stabilization of a
non-productive state. Thereby, the chemical drug-binding signal is converted,
propagated and amplified into structural changes over a distance of more than
150 Å from the proteolytic site to the ubiquitin receptor Rpn10. The direct
visualization of changes in conformational dynamics upon drug binding allows new
ways to screen and develop future allosteric proteasome inhibitors.
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