1os5
From Proteopedia
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'''Crystal structure of HCV NS5B RNA polymerase complexed with a novel non-competitive inhibitor.''' | '''Crystal structure of HCV NS5B RNA polymerase complexed with a novel non-competitive inhibitor.''' | ||
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[[Category: Wriggers, H.]] | [[Category: Wriggers, H.]] | ||
[[Category: Yu, X.]] | [[Category: Yu, X.]] | ||
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Revision as of 01:13, 3 May 2008
Crystal structure of HCV NS5B RNA polymerase complexed with a novel non-competitive inhibitor.
Overview
The virus-encoded nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase and is absolutely required for replication of the virus. NS5B exhibits significant differences from cellular polymerases and therefore has become an attractive target for anti-HCV therapy. Using a high-throughput screen, we discovered a novel NS5B inhibitor that binds to the enzyme noncompetitively with respect to nucleotide substrates. Here we report the crystal structure of NS5B complexed with this small molecule inhibitor. Unexpectedly, the inhibitor is bound within a narrow cleft on the protein's surface in the "thumb" domain, about 30 A from the enzyme's catalytic center. The interaction between this inhibitor and NS5B occurs without dramatic changes to the structure of the protein, and sequence analysis suggests that the binding site is conserved across known HCV genotypes. Possible mechanisms of inhibition include perturbation of protein dynamics, interference with RNA binding, and disruption of enzyme oligomerization.
About this Structure
1OS5 is a Single protein structure of sequence from Hepatitis c virus subtype 1b. Full crystallographic information is available from OCA.
Reference
Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme., Love RA, Parge HE, Yu X, Hickey MJ, Diehl W, Gao J, Wriggers H, Ekker A, Wang L, Thomson JA, Dragovich PS, Fuhrman SA, J Virol. 2003 Jul;77(13):7575-81. PMID:12805457 Page seeded by OCA on Sat May 3 04:13:03 2008
