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PDBsum entry 3b6c
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Transcription
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PDB id
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3b6c
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the streptomyces coelicolor tetr-Like protein actr alone and in complex with actinorhodin or the actinorhodin biosynthetic precursor (s)-Dnpa.
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Authors
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A.R.Willems,
K.Tahlan,
T.Taguchi,
K.Zhang,
Z.Z.Lee,
K.Ichinose,
M.S.Junop,
J.R.Nodwell.
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Ref.
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J Mol Biol, 2008,
376,
1377-1387.
[DOI no: ]
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PubMed id
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Abstract
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Actinorhodin, an antibiotic produced by Streptomyces coelicolor, is exported
from the cell by the ActA efflux pump. actA is divergently transcribed from
actR, which encodes a TetR-like transcriptional repressor. We showed previously
that ActR represses transcription by binding to an operator from the actA/actR
intergenic region. Importantly, actinorhodin itself or various actinorhodin
biosynthetic intermediates can cause ActR to dissociate from its operator,
leading to derepression. This suggests that ActR may mediate timely
self-resistance to an endogenously produced antibiotic by responding to one of
its biosynthetic precursors. Here, we report the structural basis for this
precursor-mediated derepression with crystal structures of homodimeric ActR by
itself and in complex with either actinorhodin or the actinorhodin biosynthetic
intermediate (S)-DNPA
[4-dihydro-9-hydroxy-1-methyl-10-oxo-3-H-naphtho-[2,3-c]-pyran-3-(S)-acetic
acid]. The ligand-binding tunnel in each ActR monomer has a striking
hydrophilic/hydrophobic/hydrophilic arrangement of surface residues that
accommodate either one hexacyclic actinorhodin molecule or two back-to-back
tricyclic (S)-DNPA molecules. Moreover, our work also reveals the strongest
structural evidence to date that TetR-mediated antibiotic resistance may have
been acquired from an antibiotic-producer organism.
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Figure 1.
Fig. 1. Actinorhodin biosynthesis and export. An initial
polyketide is transformed via multiple enzyme-catalyzed steps
into (S)-DNPA and, eventually, actinorhodin, which is exported
from the cell. The proposed mechanism of export regulation by
actinorhodin and (S)-DNPA is supported by recent studies that
show that ActR can be derepressed by these compounds.^21
Numbering of selected carbon atoms based on biosynthetic origin
is indicated. The broken line within actinorhodin indicates its
internal bilateral symmetry.
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Figure 5.
Fig. 5. The hydrogen-bonding network near the proximal
ligand-binding site. Side chains and one backbone carbonyl group
that form a hydrogen-bonding network in the ActR/(S)-DNPA
structure are shown. The molecular protein surface of the
proximal end of the ligand-binding tunnel of chain A is shown,
as is the position of the proximal (S)-DNPA molecule. Note the
proximity of the ligand carboxymethyl group and R225.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
376,
1377-1387)
copyright 2008.
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