Figure 4.
Proposed mode of action of allosteric inhibitors
A. Closed conformation - product of the cis-cleavage between the NS3 and NS4a proteins. The C-terminus of the helicase domain occupies the protease active site and stabilises the protein in an auto-inhibited conformation.
B. Open conformation - required for proteolytic activity and also reportedly required for helicase activity 31. This conformation allows substrates to access the protease active site and is inhibited by the peptidomimetic active site inhibitors such as telaprevir and boceprevir.
C. Closed conformation – Compounds binding at the protease-helicase interface stabilise the auto-inhibited conformation of the protein and block catalytic function via an allosteric mechanism.
Colour key: red oval - allosteric inhibitor; orange line - C-terminus of the helicase domain; brown line - flexible linker between the protease and helicase domains.