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PDBsum entry 4wtf
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Transferase/RNA
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PDB id
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4wtf
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References listed in PDB file
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Key reference
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Title
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Viral replication. Structural basis for RNA replication by the hepatitis c virus polymerase.
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Authors
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T.C.Appleby,
J.K.Perry,
E.Murakami,
O.Barauskas,
J.Feng,
A.Cho,
D.Fox,
D.R.Wetmore,
M.E.Mcgrath,
A.S.Ray,
M.J.Sofia,
S.Swaminathan,
T.E.Edwards.
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Ref.
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Science, 2015,
347,
771-775.
[DOI no: ]
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PubMed id
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Abstract
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Nucleotide analog inhibitors have shown clinical success in the treatment of
hepatitis C virus (HCV) infection, despite an incomplete mechanistic
understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the
details of HCV RNA replication by determining crystal structures of stalled
polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming
nucleotides, and catalytic metal ions during both primed initiation and
elongation of RNA synthesis. Our analysis revealed that highly conserved
active-site residues in NS5B position the primer for in-line attack on the
incoming nucleotide. A β loop and a C-terminal membrane-anchoring linker
occlude the active-site cavity in the apo state, retract in the primed
initiation assembly to enforce replication of the HCV genome from the 3'
terminus, and vacate the active-site cavity during elongation. We investigated
the incorporation of nucleotide analog inhibitors, including the clinically
active metabolite formed by sofosbuvir, to elucidate key molecular interactions
in the active site.
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