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2d41

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{{STRUCTURE_2d41| PDB=2d41 | SCENE= }}
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'''X-ray crystal structure of hepatitis C virus RNA-dependent RNA polymerase in complex with non-nucleoside inhibitor'''
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===X-ray crystal structure of hepatitis C virus RNA-dependent RNA polymerase in complex with non-nucleoside inhibitor===
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==Overview==
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The RNA-dependent RNA polymerase (NS5B) from hepatitis C virus (HCV) is a key enzyme in HCV replication. NS5B is a major target for the development of antiviral compounds directed against HCV. Here we present the structures of three thiophene-based non-nucleoside inhibitors (NNIs) bound non-covalently to NS5B. Each of the inhibitors binds to NS5B non-competitively to a common binding site in the "thumb" domain that is approximately 35 Angstroms from the polymerase active site located in the "palm" domain. The three compounds exhibit IC(50) values in the range of 270 nM to 307 nM and have common binding features that result in relatively large conformational changes of residues that interact directly with the inhibitors as well as for other residues adjacent to the binding site. Detailed comparisons of the unbound NS5B structure with those having the bound inhibitors present show that residues Pro495 to Arg505 (the N terminus of the "T" helix) exhibit some of the largest changes. It has been reported that Pro495, Pro496, Val499 and Arg503 are part of the guanosine triphosphate (GTP) specific allosteric binding site located in close proximity to our binding site. It has also been reported that the introduction of mutations to key residues in this region (i.e. Val499Gly) ablate in vivo sub-genomic HCV RNA replication. The details of NS5B polymerase/inhibitor binding interactions coupled with the observed induced conformational changes provide new insights into the design of novel NNIs of HCV.
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(as it appears on PubMed at http://www.pubmed.gov), where 16828488 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16828488}}
==About this Structure==
==About this Structure==
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[[Category: Rna polymerase]]
[[Category: Rna polymerase]]
[[Category: X-ray crystallography]]
[[Category: X-ray crystallography]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 23:39:51 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 23:40:54 2008''

Revision as of 20:41, 27 July 2008

Image:2d41.png

Template:STRUCTURE 2d41

X-ray crystal structure of hepatitis C virus RNA-dependent RNA polymerase in complex with non-nucleoside inhibitor

Template:ABSTRACT PUBMED 16828488

About this Structure

2D41 is a Single protein structure of sequence from Hepatitis c virus. Full crystallographic information is available from OCA.

Reference

Non-nucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition., Biswal BK, Wang M, Cherney MM, Chan L, Yannopoulos CG, Bilimoria D, Bedard J, James MN, J Mol Biol. 2006 Aug 4;361(1):33-45. Epub 2006 Jun 16. PMID:16828488

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