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PDBsum entry 3dll
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Contents |
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218 a.a.
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205 a.a.
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197 a.a.
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177 a.a.
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171 a.a.
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70 a.a.
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142 a.a.
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134 a.a.
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141 a.a.
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136 a.a.
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113 a.a.
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104 a.a.
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108 a.a.
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117 a.a.
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94 a.a.
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127 a.a.
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93 a.a.
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110 a.a.
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175 a.a.
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84 a.a.
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72 a.a.
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66 a.a.
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55 a.a.
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58 a.a.
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53 a.a.*
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46 a.a.*
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63 a.a.*
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37 a.a.
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* C-alpha coords only
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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 oxazolidinone antibiotics perturb the ribosomal peptidyl-Transferase center and effect tRNA positioning.
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Authors
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D.N.Wilson,
F.Schluenzen,
J.M.Harms,
A.L.Starosta,
S.R.Connell,
P.Fucini.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
13339-13344.
[DOI no: ]
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PubMed id
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Abstract
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The oxazolidinones represent the first new class of antibiotics to enter into
clinical usage within the past 30 years, but their binding site and mechanism of
action has not been fully characterized. We have determined the crystal
structure of the oxazolidinone linezolid bound to the Deinococcus radiodurans
50S ribosomal subunit. Linezolid binds in the A site pocket at the
peptidyltransferase center of the ribosome overlapping the aminoacyl moiety of
an A-site bound tRNA as well as many clinically important antibiotics. Binding
of linezolid stabilizes a distinct conformation of the universally conserved 23S
rRNA nucleotide U2585 that would be nonproductive for peptide bond formation. In
conjunction with available biochemical data, we present a model whereby
oxazolidinones impart their inhibitory effect by perturbing the correct
positioning of tRNAs on the ribosome.
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Figure 1.
The binding site of oxazolidinones. (A) Secondary structure
of the peptidyltransferase ring of the 23S rRNA from D.
radiodurans with the mutation sites in bacteria (blue) and
archaea (purple) that confer resistance to oxazolidinones
indicated with E. coli numbering. Nucleotides that directly
interact with linezolid are shaded light blue, and the mutations
sites associated with resistance for chloramphenicol (cam) (45,
46), anisomycin (aniso) (47, 48), and pleuromutilins (pleuro)
(49) are shown. (B) Interface view of the D. radiodurans 50S
subunit with the binding position of linezolid (red) and
landmark proteins L1 and L11 as indicated. (C) Chemical
structure of linezolid, highlighting the three aromatic rings
(A–C) and the acetamidomethyl tail. (D) View of linezolid
(pink) within the binding pocket formed by eight universally
conserved nucleotides (blue) of the 23S rRNA. The arrow
indicates tunnel direction.
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Figure 4.
Linezolid overlaps A-site ligands at the peptidyltransferase
center. (A–F) Comparison of the binding site of linezolid
(pink) on D50S (A) with chloramphenicol (PDB ID code 1K01;
green) (6) (B), anisomycin (PDB ID code 1K73; olive) (3) (C),
tiamulin (PDB ID code 1XBP; teal) (7) (D), clindamycin (PDB ID
code 1JZX; magenta) (6) (E), and A- (yellow) and P-site (orange)
phenylalanyl-tRNA CCA-end mimics (PDB ID code 1VQN) (27) (F). In
all cases, U2585 (blue) from the D50S-linezolid structure is
shown for reference.
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