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- W2130832885 abstract "The hepatitis C virus (HCV) nonstructural (NS)3-NS4A serine protease heterocomplex is a prime target for development of novel HCV therapies, due to its essential role in maturation of the viral polyprotein. While the mode of substrate/inhibitor recognition of the HCV NS3/NS4A serine protease has been extensively studied in vitro, important molecular aspects of the mechanism of action for this membrane-bound multifunctional enzyme remain unresolved in vivo. In particular, what influence does membrane association exert on the specificity and catalysis of NS3-4A protease? To carry out this study, we developed a specific and sensitive protease assay using a unique internally quenched fluorogenic substrate (IQFS). Our IQFS enables for the first time the direct, specific detection of NS3-4A protease activity within membrane fractions isolated from human cells expressing NS3-4A and the determination of its steady-state kinetic parameters, which were found to be Km = 51 ± 3 μM and kcat = 0.39 min-1. We also show that our fluorescence-based bioassay can be used to evaluate specifically the potency and mode of action of NS3-4A directed inhibitors, such as in the case of a known NS3-4A substrate-analogue inhibitor (Ki = 22 nM). Our results indicate that the membrane anchoring of NS3 by NS4A does not affect the substrate/inhibitor recognition by the NS3-4A protease domain. Further investigation may reveal whether membrane association could be important for regulating other enzymatic activities associated with NS3 (e.g., helicase and/or ATPase) and/or regulating the recently proposed cross-talk between the protease and helicase activities." @default.
- W2130832885 created "2016-06-24" @default.
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- W2130832885 date "2005-04-08" @default.
- W2130832885 modified "2023-10-15" @default.
- W2130832885 title "Enzymatic Characterization of Membrane-Associated Hepatitis C Virus NS3-4A Heterocomplex Serine Protease Activity Expressed in Human Cells" @default.
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- W2130832885 doi "https://doi.org/10.1021/bi047408j" @default.
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