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PDBsum entry 1os5
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis c virus ns5b RNA polymerase enzyme.
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Authors
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R.A.Love,
H.E.Parge,
X.Yu,
M.J.Hickey,
W.Diehl,
J.Gao,
H.Wriggers,
A.Ekker,
L.Wang,
J.A.Thomson,
P.S.Dragovich,
S.A.Fuhrman.
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Ref.
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J Virol, 2003,
77,
7575-7581.
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PubMed id
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Abstract
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The virus-encoded nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is
an RNA-dependent RNA polymerase and is absolutely required for replication of
the virus. NS5B exhibits significant differences from cellular polymerases and
therefore has become an attractive target for anti-HCV therapy. Using a
high-throughput screen, we discovered a novel NS5B inhibitor that binds to the
enzyme noncompetitively with respect to nucleotide substrates. Here we report
the crystal structure of NS5B complexed with this small molecule inhibitor.
Unexpectedly, the inhibitor is bound within a narrow cleft on the protein's
surface in the "thumb" domain, about 30 A from the enzyme's catalytic center.
The interaction between this inhibitor and NS5B occurs without dramatic changes
to the structure of the protein, and sequence analysis suggests that the binding
site is conserved across known HCV genotypes. Possible mechanisms of inhibition
include perturbation of protein dynamics, interference with RNA binding, and
disruption of enzyme oligomerization.
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Secondary reference #1
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Title
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Hepatitis c virus (hcv) ns5b RNA polymerase and mutants thereof.
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Authors
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R.A.Love,
H.E.Parge,
M.J.Hickey,
X.Yu,
S.A.Fuhrman,
W.Diehl,
J.Gao.
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Ref.
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european patent application ...
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