کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2188981 1096192 2006 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Non-nucleoside Inhibitors Binding to Hepatitis C Virus NS5B Polymerase Reveal a Novel Mechanism of Inhibition
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیولوژی سلول
پیش نمایش صفحه اول مقاله
Non-nucleoside Inhibitors Binding to Hepatitis C Virus NS5B Polymerase Reveal a Novel Mechanism of Inhibition
چکیده انگلیسی

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 ∼35 Å from the polymerase active site located in the “palm” domain. The three compounds exhibit IC50 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Biology - Volume 361, Issue 1, 4 August 2006, Pages 33–45
نویسندگان
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