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PDBsum entry 6e5b
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Contents |
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229 a.a.
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245 a.a.
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227 a.a.
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230 a.a.
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236 a.a.
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244 a.a.
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241 a.a.
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218 a.a.
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204 a.a.
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196 a.a.
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203 a.a.
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213 a.a.
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214 a.a.
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199 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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Design and evaluation of highly selective human immunoproteasome inhibitors reveal a compensatory process that preserves immune cell viability.
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Authors
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E.Ladi,
C.Everett,
C.E.Stivala,
B.E.Daniels,
M.R.Durk,
S.F.Harris,
M.P.Huestis,
H.E.Purkey,
S.T.Staben,
M.Augustin,
M.Blaesse,
S.Steinbacher,
C.Eidenschenk,
R.Pappu,
M.Siu.
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Ref.
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J Med Chem, 2019,
62,
7032-7041.
[DOI no: ]
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PubMed id
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DOI number
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Abstract
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The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in
off-label trials of Systemic Lupus Erythematosus. One potential mechanism of
this clinical benefit is from the depletion of pathogenic immune cells
(plasmablasts and plasmacytoid dendritic cells). However, bortezomib is
cytotoxic against nonimmune cells, which limits its use for autoimmune diseases.
An attractive alternative is to selectively inhibit the immune cell-specific
immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic
cells. Here, we disclose the development of highly subunit-selective
immunoproteasome inhibitors using insights obtained from the first bona fide
human immunoproteasome cocrystal structures. Evaluation of these inhibitors
revealed that immunoproteasome-specific inhibition does not lead to immune cell
death as anticipated and that targeting viability requires inhibition of both
immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments
confirmed upregulation of the constitutive proteasome upon disruption of the
immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition
alone is not a suitable approach to deplete immune cells.
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