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PDBsum entry 4y3c
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Viral protein
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PDB id
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4y3c
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Enzyme class 1:
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E.C.2.7.7.48
- RNA-directed Rna polymerase.
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Reaction:
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RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
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RNA(n)
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+
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ribonucleoside 5'-triphosphate
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=
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RNA(n+1)
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+
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diphosphate
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Enzyme class 2:
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E.C.3.4.22.28
- picornain 3C.
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Reaction:
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Selective cleavage of Gln-|-Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly.
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Enzyme class 3:
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E.C.3.6.4.13
- Rna helicase.
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Reaction:
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ATP + H2O = ADP + phosphate + H+
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ATP
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+
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H2O
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=
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ADP
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+
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phosphate
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Plos Pathog
11:e1004733
(2015)
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PubMed id:
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The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family.
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L.van der Linden,
L.Vives-Adrián,
B.Selisko,
C.Ferrer-Orta,
X.Liu,
K.Lanke,
R.Ulferts,
A.M.De Palma,
F.Tanchis,
N.Goris,
D.Lefebvre,
K.De Clercq,
P.Leyssen,
C.Lacroix,
G.Pürstinger,
B.Coutard,
B.Canard,
D.D.Boehr,
J.J.Arnold,
C.E.Cameron,
N.Verdaguer,
J.Neyts,
F.J.van Kuppeveld.
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ABSTRACT
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The genus Enterovirus of the family Picornaviridae contains many important human
pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for
which no antiviral drugs are available. The viral RNA-dependent RNA polymerase
is an attractive target for antiviral therapy. Nucleoside-based inhibitors have
broad-spectrum activity but often exhibit off-target effects. Most
non-nucleoside inhibitors (NNIs) target surface cavities, which are structurally
more flexible than the nucleotide-binding pocket, and hence have a more narrow
spectrum of activity and are more prone to resistance development. Here, we
report a novel NNI, GPC-N114
(2,2'-[(4-chloro-1,2-phenylene)bis(oxy)]bis(5-nitro-benzonitrile)) with
broad-spectrum activity against enteroviruses and cardioviruses (another genus
in the picornavirus family). Surprisingly, coxsackievirus B3 (CVB3) and
poliovirus displayed a high genetic barrier to resistance against GPC-N114. By
contrast, EMCV, a cardiovirus, rapidly acquired resistance due to mutations in
3Dpol. In vitro polymerase activity assays showed that GPC-N114 i) inhibited the
elongation activity of recombinant CVB3 and EMCV 3Dpol, (ii) had reduced
activity against EMCV 3Dpol with the resistance mutations, and (iii) was most
efficient in inhibiting 3Dpol when added before the RNA template-primer duplex.
Elucidation of a crystal structure of the inhibitor bound to CVB3 3Dpol
confirmed the RNA-binding channel as the target for GPC-N114. Docking studies of
the compound into the crystal structures of the compound-resistant EMCV 3Dpol
mutants suggested that the resistant phenotype is due to subtle changes that
interfere with the binding of GPC-N114 but not of the RNA template-primer. In
conclusion, this study presents the first NNI that targets the RNA template
channel of the picornavirus polymerase and identifies a new pocket that can be
used for the design of broad-spectrum inhibitors. Moreover, this study provides
important new insight into the plasticity of picornavirus polymerases at the
template binding site.
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Links
