NS5B: Difference between revisions
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[http://www.nature.com/nrmicro/journal/v5/n6/fig_tab/nrmicro1645_F4.html This image] is a depiction of each of the protein products of NS5B genomic translation. The proteins coded for by the hepatitis C virus (HCV) genome all associate with the ER membrane. The proteins are translated as one large poly-protein that is enzymatically cleaved by both host and viral proteases. Of the several proteins that are coded for by HCV, three functions have been identified as relevant drug targets, these are the NS3 protease and helicase domains and the NS5B RNA dependent RNA polymerase. Currently the therapy for HCV is interferon therapy often in combination with ribavirin. This therapy however is inadequate; it is not effective in each genotype of HCV, it is not well tolerated, and is expensive. For these reasons many academic and industrial laboratories have been working on developing novel inhibitors of NS5B. | [http://www.nature.com/nrmicro/journal/v5/n6/fig_tab/nrmicro1645_F4.html This image] is a depiction of each of the protein products of NS5B genomic translation. The proteins coded for by the hepatitis C virus (HCV) genome all associate with the ER membrane. The proteins are translated as one large poly-protein that is enzymatically cleaved by both host and viral proteases. Of the several proteins that are coded for by HCV, three functions have been identified as relevant drug targets, these are the NS3 protease and helicase domains and the NS5B RNA dependent RNA polymerase. Currently the therapy for HCV is interferon therapy often in combination with ribavirin. This therapy however is inadequate; it is not effective in each genotype of HCV, it is not well tolerated, and is expensive. For these reasons many academic and industrial laboratories have been working on developing novel inhibitors of NS5B. | ||
<scene name='NS5B/Cv/2'>Much of the x-ray crystallography work that has gone into NS5B to date</scene> (Ligands are from: 1C2P, 1CSJ, 1GX5, 1GX6, 1NB4, 1NB6, 1NB7, 1HNU, 1NHV, 1OS5, 1QUV, 1YUY, 1YV2, 1YVF, 1YVX, 1YVZ, 1Z4U, 2AWZ, 2AX0, 2AX1, 2BRK, 2BRL, 2D3U, 2D3Z, 2D41, 2GIQ, 2GIR, 2HWH, 2HWI, 2I1R, 2IJN, 2JC0, 2JC1, 3BR9, 3BSA, 3BSC, 3CIZ, 3CJ0, 3CJ2, 3CJ3, 3CJ4, 3CJ5). Superpositions in the scene by Rould MA, and Villanueva NL. Each of the forty three structures included in the superposition contain at least one ligand, the ligands range from ions and small molecules to nucleotides and non-nucleoside analogue inhibitors. Positioning the structure in the familiar orientation with the <scene name='NS5B/Ns5b_with_ligands/3'>domains</scene> colored as above, it is obvious that there are two primary areas where ligands are clustering. Several nucleotides, oligonucleotides and non-nucleoside analogue inhibitors can be found near the <scene name='NS5B/Ns5b_with_ligands/4'>active site</scene>. There is another site that is about 30-35Å from the active site, an <scene name='NS5B/Ns5b_with_ligands/5'>allosteric site</scene>, where again ligands are clustering. There is a rGTP binding site here that seems to activate the enzyme and a nearby site where inhibitors bind and disrupt the activity of the enzyme. | |||
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The inhibitors that bind near the <scene name='NS5B/Ns5b_with_ligands/4'>active site</scene> are thought to work by disrupting the ''primer grip'' site causing an inability of the enzyme to efficiently hold and extend a growing primer strand. The inhibitors that bind near the <scene name='NS5B/Ns5b_with_ligands/5'>allosteric site</scene> work through a poorly understood mechanism, several explanations for their ability to inhibit the enzyme have been proposed. The commonly proposed explanations are that these inhibitors lock the enzyme in an inactive conformation, inhibit binding of the rGTP that binds in the area and has been shown to stimulate activity, or that this interface is critical in protein-protein interactions and disruption of these interactions by the inhibitors disrupts an oligomerization of several NS5B protomers thus making each less efficient. | The inhibitors that bind near the <scene name='NS5B/Ns5b_with_ligands/4'>active site</scene> are thought to work by disrupting the ''primer grip'' site causing an inability of the enzyme to efficiently hold and extend a growing primer strand. The inhibitors that bind near the <scene name='NS5B/Ns5b_with_ligands/5'>allosteric site</scene> work through a poorly understood mechanism, several explanations for their ability to inhibit the enzyme have been proposed. The commonly proposed explanations are that these inhibitors lock the enzyme in an inactive conformation, inhibit binding of the rGTP that binds in the area and has been shown to stimulate activity, or that this interface is critical in protein-protein interactions and disruption of these interactions by the inhibitors disrupts an oligomerization of several NS5B protomers thus making each less efficient. | ||
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For additional information, see: [[Viral Infections]] | For additional information, see: [[Viral Infections]] | ||
<br /> | <br /> | ||
</StructureSection> | |||
== | ==References== | ||
<ref group="xtra">PMID:16824756</ref><references group="xtra"/> | <ref group="xtra">PMID:16824756</ref><references group="xtra"/> | ||
<ref group="xtra">PMID:1849654</ref><references group="xtra"/> | <ref group="xtra">PMID:1849654</ref><references group="xtra"/> | ||
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<ref group="xtra">PMID:12509436</ref><references group="xtra"/> | <ref group="xtra">PMID:12509436</ref><references group="xtra"/> | ||
<ref group="xtra">PMID:15863301</ref><references group="xtra"/> | <ref group="xtra">PMID:15863301</ref><references group="xtra"/> | ||
[[Category: Ns5b]] | [[Category: Ns5b]] | ||
[[Category: Hepatitis c virus]] | [[Category: Hepatitis c virus]] | ||
[[Category: RNA-directed RNA polymerase]] | [[Category: RNA-directed RNA polymerase]] | ||
[[Category: Hcv rna polymerase]] | [[Category: Hcv rna polymerase]] | ||
