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PDBsum entry 4qlq
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Hydrolase/hydrolase inhibitor
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PDB id
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4qlq
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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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Structure-Based design of β1i or β5i specific inhibitors of human immunoproteasomes.
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Authors
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G.De bruin,
E.M.Huber,
B.T.Xin,
E.J.Van rooden,
K.Al-Ayed,
K.B.Kim,
A.F.Kisselev,
C.Driessen,
M.Van der stelt,
G.A.Van der marel,
M.Groll,
H.S.Overkleeft.
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Ref.
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J Med Chem, 2014,
57,
6197-6209.
[DOI no: ]
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PubMed id
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Abstract
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Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c,
β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i,
β2i, β5i (incorporated into immunoproteasomes), and the
thymoproteasome-specific subunit β5t. Extensive research in the past decades
has yielded numerous potent proteasome inhibitors including compounds currently
used in the clinic to treat multiple myeloma and mantle cell lymphoma.
Proteasome inhibitors that selectively target combinations of β1c/β1i,
β2c/β2i, or β5c/β5i are available, yet ligands truly selective for a single
proteasome activity are scarce. In this work we report the development of
cell-permeable β1i and β5i selective inhibitors that outperform existing leads
in terms of selectivity and/or potency. These compounds are the result of a
rational design strategy using known inhibitors as starting points and
introducing structural features according to the X-ray structures of the murine
constitutive and immunoproteasome 20S core particles.
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