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| [[Image:2giq.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2giq| PDB=2giq | SCENE= }} | | {{STRUCTURE_2giq| PDB=2giq | SCENE= }} |
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| '''Hepatitis C virus RNA-dependent RNA polymerase NS5B with NNI-2 inhibitor'''
| | ===Hepatitis C virus RNA-dependent RNA polymerase NS5B with NNI-2 inhibitor=== |
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| ==Overview==
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| Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains. After a single treatment with a thumb site inhibitor (thiophene-2-carboxylic acid NNI-1), resistant HCV replicon variants emerged that contained mutations at residues Leu419, Met423, and Ile482 in the polymerase thumb domain. Binding studies using wild-type (WT) and mutant enzymes and structure-based modeling showed that the mechanism of resistance is through the reduced binding of the inhibitor to the mutant enzymes. Combined treatment with a thumb- and a palm-binding polymerase inhibitor had a dramatic impact on the number of replicon colonies able to replicate in the presence of both inhibitors. A more exact characterization through molecular cloning showed that 97.7% of replicons contained amino acid substitutions that conferred resistance to either of the inhibitors. Of those, 65% contained simultaneously multiple amino acid substitutions that conferred resistance to both inhibitors. Double-mutant replicons Met414Leu and Met423Thr were predominantly selected, which showed reduced replication capacity compared to the WT replicon. These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16731953}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16731953 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16731953}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Rna-dependent rna polymerase]] | | [[Category: Rna-dependent rna polymerase]] |
| [[Category: Transferase]] | | [[Category: Transferase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:09:11 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 06:02:05 2008'' |
