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PDBsum entry 2fhh
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Contents |
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(+ 8 more)
220 a.a.
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(+ 8 more)
222 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 of the mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate.
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Authors
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G.Hu,
G.Lin,
M.Wang,
L.Dick,
R.M.Xu,
C.Nathan,
H.Li.
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Ref.
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Mol Microbiol, 2006,
59,
1417-1428.
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PubMed id
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Abstract
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Mycobacterium tuberculosis (Mtb) has the remarkable ability to resist killing by
human macrophages. The 750 kDa proteasome, not available in most eubacteria
except Actinomycetes, appears to contribute to Mtb's resistance. The crystal
structure of the Mtb proteasome at 3.0 A resolution reveals a substrate-binding
pocket with composite features of the distinct beta1, beta2 and beta5 substrate
binding sites of eukaryotic proteasomes, accounting for the broad specificity of
the Mtb proteasome towards oligopeptides described in the companion article [Lin
et al. (2006), Mol Microbiol doi:10.1111/j.1365-2958.2005.05035.x]. The
substrate entrance at the end of the cylindrical proteasome appears open in the
crystal structure due to partial disorder of the alpha-subunit N-terminal
residues. However, cryo-electron microscopy of the core particle reveals a
closed end, compatible with the density observed in negative-staining electron
microscopy that depended on the presence of the N-terminal octapetides of the
alpha-subunits in the companion article, suggesting that the Mtb proteasome has
a gated structure. We determine for the first time the proteasomal inhibition
mechanism of the dipeptidyl boronate
N-(4-morpholine)carbonyl-beta-(1-naphthyl)-L-alanine-L-leucine boronic acid
(MLN-273), an analogue of the antimyeloma drug bortezomib. The structure
improves prospects for designing Mtb-specific proteasomal inhibitors as a novel
approach to chemotherapy of tuberculosis.
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