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PDBsum entry 2fum
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References listed in PDB file
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Key reference
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Title
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The structure of pknb in complex with mitoxantrone, An ATP-Competitive inhibitor, Suggests a mode of protein kinase regulation in mycobacteria.
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Authors
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A.Wehenkel,
P.Fernandez,
M.Bellinzoni,
V.Catherinot,
N.Barilone,
G.Labesse,
M.Jackson,
P.M.Alzari.
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Ref.
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FEBS Lett, 2006,
580,
3018-3022.
[DOI no: ]
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PubMed id
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Abstract
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Mycobacterium tuberculosis PknB is an essential receptor-like protein kinase
involved in cell growth control. Here, we demonstrate that mitoxantrone, an
anthraquinone derivative used in cancer therapy, is a PknB inhibitor capable of
preventing mycobacterial growth. The structure of the complex reveals that
mitoxantrone partially occupies the adenine-binding pocket in PknB, providing a
framework for the design of compounds with potential therapeutic applications.
PknB crystallizes as a 'back-to-back' homodimer identical to those observed in
other structures of PknB in complex with ATP analogs. This organization
resembles that of the RNA-dependent protein kinase PKR, suggesting a mechanism
for kinase activation in mycobacteria.
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Figure 2.
Fig. 2. Structure of the PknB-mitoxantrone complex. (a)
Superposition of the PknB-mitoxantrone complex (in yellow) and
the PknB-AMPPCP complex (1O6Y, in cyan). Note the movement of
the Gly-rich loop (black arrow). (b) Observed (yellow) and
predicted (thin lines) orientations of mitoxantrone within the
adenosine-binding cavity (represented as a molecular surface).
The electron density map for the inhibitor is contoured at 1σ.
(c) Schematic view (represented as in Ref. [26]) of the PknB
ATP-binding site showing hydrogen bonding interactions with both
the inhibitor (in blue) and AMP-PCP (PDB code 1O6Y).
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Figure 3.
Fig. 3. The conserved PknB homodimer. (a) Superposition of
the two crystallographically independent homodimers from the
PknB-mitoxantrone complex (in red and green) with those observed
in the PknB-nucleotide complexes 1O6Y [3] (in blue) and 1MRU [4]
(in yellow). (b) Overall view of the PknB monomer (rotated
90° along the vertical axis with respect to the right
monomer in Fig. 3a), color-coded according to amino acid
conservation (red: highly conserved) in 39 PknB-like protein
sequences from 35 different bacterial species (Bacillus
anthracis, B. cereus, B. clausii, B. licheniformis, B. subtilis,
Bifidobacterium longum, Clostridium acetobutylicum, C.
perfringens, C. tetani, Corynebacterium diphtheriae, C.
efficiens, C. glutamicum, Enterococcus faecalis, Geobacillus
kaustophilus, Lactobacillus acidophilus, L. johnsonii, Listeria
monocytogenes, Mycobacterium avium, M. bovis, M. leprae, M.
tuberculosis, Nocardia farcinica, Nocardioides, Leifsonia xyli,
Oceanobacillus iheyensis, Propionibacterium acnes,
Staphylococcus haemolyticus, S. saprophyticus, Streptococcus
agalactiae, S. mutans, S. pyogenes, Streptomyces coelicolor,
Symbiobacterium thermophilum, Thermoanaerobacter tengcongensis,
Thermobifida fusca). (c) Comparison of the PknB and
RNA-dependent PKR dimer interfaces. The side-chain residues
belonging to the interfaces are shown (PknB color-coded as in
(b)).
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The above figures are
reprinted
by permission from the Federation of European Biochemical Societies:
FEBS Lett
(2006,
580,
3018-3022)
copyright 2006.
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