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PDBsum entry 3cc4
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237 a.a.
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337 a.a.
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246 a.a.
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140 a.a.
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172 a.a.
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119 a.a.
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29 a.a.
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160 a.a.
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70 a.a.
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142 a.a.
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132 a.a.
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145 a.a.
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194 a.a.
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186 a.a.
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115 a.a.
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143 a.a.
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95 a.a.
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150 a.a.
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81 a.a.
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119 a.a.
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53 a.a.
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65 a.a.
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154 a.a.
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82 a.a.
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142 a.a.
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73 a.a.
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56 a.a.
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46 a.a.
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92 a.a.
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 _SR
×108
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 _NA
×75
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 _CL
×22
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_MG
×93
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 _CD
×5
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 __K
×2
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References listed in PDB file
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Key reference
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Title
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Mutations outside the anisomycin-Binding site can make ribosomes drug-Resistant.
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Authors
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G.Blaha,
G.Gürel,
S.J.Schroeder,
P.B.Moore,
T.A.Steitz.
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Ref.
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J Mol Biol, 2008,
379,
505-519.
[DOI no: ]
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PubMed id
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Abstract
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Eleven mutations that make Haloarcula marismortui resistant to anisomycin, an
antibiotic that competes with the amino acid side chains of aminoacyl tRNAs for
binding to the A-site cleft of the large ribosomal unit, have been identified in
23S rRNA. The correlation observed between the sensitivity of H. marismortui to
anisomycin and the affinity of its large ribosomal subunits for the drug
indicates that its response to anisomycin is determined primarily by the binding
of the drug to its large ribosomal subunit. The structures of large ribosomal
subunits containing resistance mutations show that these mutations can be
divided into two classes: (1) those that interfere with specific drug-ribosome
interactions and (2) those that stabilize the apo conformation of the A-site
cleft of the ribosome relative to its drug-bound conformation. The
conformational effects of some mutations of the second kind propagate through
the ribosome for considerable distances and are reversed when A-site substrates
bind to the ribosome.
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Figure 2.
Fig. 2. A global view of the positions of the bases, the
mutation of which cause anisomycin resistance in H. marismortui.
The drug (gold with spherical atoms) is shown surrounded by the
bases, the mutation of which leads to drug resistance (red). The
backbone connecting the bases is indicated in gray. The
positions occupied by the CCA end of P-site-bound tRNA (orange)
and A-site-bound tRNA (green) are shown for orientation. E. coli
numbering is used for all bases.
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Figure 5.
Fig. 5. The effect of A-site substrate binding on the
conformation of large ribosomal subunits containing the mutation
G2581A. (a) Comparison of the conformation of the 2581 region of
wild-type ribosomes (gray) with that of the G2581A mutant
(green). Also included in the figure is CC-puromycin (blue
green) as reference for the binding site of amino acylated tRNA
to the A-site. (b) Comparison of the structure of G2581A mutant
(green) and CC-puromycin bound to a large ribosomal subunit of
wild type (gold). (c) Comparison of the structures of G2581A
mutant (green) and of CC-puromycin bound to G2581A (khaki) with
overlaid (F[G2581A]−F[G2581A CC-puromycin]) difference
electron density, which was computed by using as amplitudes the
differences observed between the data obtained from G2581A
crystals that include the analog and the data obtained from
G2581A crystals that lack the analog. Positive features were
contoured at + 4σ (blue), and negative features were contoured
at − 4σ (red).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
379,
505-519)
copyright 2008.
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Secondary reference #1
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Title
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Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit.
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Authors
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J.L.Hansen,
P.B.Moore,
T.A.Steitz.
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Ref.
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J Mol Biol, 2003,
330,
1061-1075.
[DOI no: ]
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PubMed id
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Figure 3.
Figure 3. Electron density maps. Unbiased F[o] -F[c]
difference Fourier maps (gray netting) contoured at 3.0s reveal
the location, orientation, and conformation of these
antibiotics. (a), (b) Nucleotides of ribosomal RNA (gray sticks)
that are either protected or deprotected by the anisomycin (a)
or chloramphenicol (b) from chemical modification (green) or
that upon mutation confer resistance to the given antibiotic
(orange) are provided for context. (c) The placement and
conformation of virginiamycin M (blue) in the corresponding
doughnut shaped electron density is unambiguous. (d) Blasticidin
S (purple) binds at two sites, but density for the second site
is weaker and incomplete. (e) Sparsomycin (green) binds only in
the presence of a P-site bound substrate (orange). A2637 (2602)
(gray stick) is apparent in the difference map because it
changes conformation upon substrate binding.
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Figure 7.
Figure 7. Sparsomycin binding site. Sparsomycin (green) is
sandwiched between the CCA end of P-site bound substrate
analogue, CCA-phe-cap-biotin (large spheres) and the base of
A2637 (2602) (gray sticks). Hydrogen bonds and ionic
interactions are shown as dotted lines. A magnesium ion is
purple and water molecules are small red spheres. The sulfur
(yellow) containing tail of sparsomycin enters the active-site
hydrophobic crevice between A2486 (2451) (gray sticks) and C2487
(2452) (orange sticks, resistance mutation).
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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