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PDBsum entry 4obc
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Viral protein, transferase
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PDB id
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4obc
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References listed in PDB file
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Key reference
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Title
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Molecular and structural basis for the roles of hepatitis c virus polymerase ns5b amino acids 15, 223, And 321 in viral replication and drug resistance.
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Authors
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A.M.Lam,
T.E.Edwards,
R.T.Mosley,
E.Murakami,
S.Bansal,
C.Lugo,
H.Bao,
M.J.Otto,
M.J.Sofia,
P.A.Furman.
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Ref.
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Antimicrob Agents Chemother, 2014,
58,
6861-6869.
[DOI no: ]
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PubMed id
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Abstract
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Resistance to the 2'-F-2'-C-methylguanosine monophosphate nucleotide hepatitis C
virus (HCV) inhibitors PSI-352938 and PSI-353661 was associated with a
combination of amino acid changes (changes of S to G at position 15 [S15G],
C223H, and V321I) within the genotype 2a nonstructural protein 5B (NS5B), an
RNA-dependent RNA polymerase. To understand the role of these residues in viral
replication, we examined the effects of single and multiple point mutations on
replication fitness and inhibition by a series of nucleotide analog inhibitors.
An acidic residue at position 15 reduced replicon fitness, consistent with its
proximity to the RNA template. A change of the residue at position 223 to an
acidic or large residue reduced replicon fitness, consistent with its proposed
proximity to the incoming nucleoside triphosphate (NTP). A change of the residue
at position 321 to a charged residue was not tolerated, consistent with its
position within a hydrophobic cavity. This triple resistance mutation was
specific to both genotype 2a virus and 2'-F-2'-C-methylguanosine inhibitors. A
crystal structure of the NS5B S15G/C223H/V321I mutant of the JFH-1 isolate
exhibited rearrangement to a conformation potentially consistent with short
primer-template RNA binding, which could suggest a mechanism of resistance
accomplished through a change in the NS5B conformation, which was better
tolerated by genotype 2a virus than by viruses of other genotypes.
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