2gir
From Proteopedia
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|PDB= 2gir |SIZE=350|CAPTION= <scene name='initialview01'>2gir</scene>, resolution 1.9Å | |PDB= 2gir |SIZE=350|CAPTION= <scene name='initialview01'>2gir</scene>, resolution 1.9Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=NN3:3-{ISOPROPYL[(TRANS-4-METHYLCYCLOHEXYL)CARBONYL]AMINO}-5-PHENYLTHIOPHENE-2-CARBOXYLIC ACID'>NN3</scene> | + | |LIGAND= <scene name='pdbligand=NN3:3-{ISOPROPYL[(TRANS-4-METHYLCYCLOHEXYL)CARBONYL]AMINO}-5-PHENYLTHIOPHENE-2-CARBOXYLIC+ACID'>NN3</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span> |
|GENE= NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10239 Viruses]) | |GENE= NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10239 Viruses]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2giq|2GIQ]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2gir FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gir OCA], [http://www.ebi.ac.uk/pdbsum/2gir PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2gir RCSB]</span> | ||
}} | }} | ||
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[[Category: Viruses]] | [[Category: Viruses]] | ||
[[Category: Harris, S F.]] | [[Category: Harris, S F.]] | ||
| - | [[Category: NN3]] | ||
[[Category: hcv]] | [[Category: hcv]] | ||
[[Category: hepatitis]] | [[Category: hepatitis]] | ||
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[[Category: transferase rna-dependent rna polymerase]] | [[Category: transferase rna-dependent rna polymerase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:17:09 2008'' |
Revision as of 00:17, 31 March 2008
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| , resolution 1.9Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Gene: | NS5B (Viruses) | ||||||
| Activity: | RNA-directed RNA polymerase, with EC number 2.7.7.48 | ||||||
| Related: | 2GIQ
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Hepatitis C virus RNA-dependent RNA polymerase NS5B with NNI-1 inhibitor
Overview
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.
About this Structure
2GIR is a Single protein structure of sequence from Viruses. Full crystallographic information is available from OCA.
Reference
Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus., Le Pogam S, Kang H, Harris SF, Leveque V, Giannetti AM, Ali S, Jiang WR, Rajyaguru S, Tavares G, Oshiro C, Hendricks T, Klumpp K, Symons J, Browner MF, Cammack N, Najera I, J Virol. 2006 Jun;80(12):6146-54. PMID:16731953
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