Avoiding drug resistance against HCV NS3/4A protease inhibitors

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding.

The protein crystallized is a single-chain construct of protease domain of hepatitis C virus NS3/4A, with cofactor 4A covalently linked at the N-terminus.
NS4A (UNP residues 1678-1688), NS3 (UNP residues 1027-1657)

GSHMASMKKKGSVVIVGRINLSGDTAYAQQTRGEEGCQETSQTGRDKNQVEGEVQIVSTATQTFLATSINGVLWTVYHGA
GTRTIASPKGPVTQMYTNVDKDLVGWQAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSA
GGPLLCPAGHAVGIFRAAVSTRGVAKAVDFIPVESLETTMRSP

100mM MES buffer pH 6.5, 4% (w/v) ammonium sulfate, 20-26% PEG 3350, VAPOR DIFFUSION, HANGING DROP, temperature 298K

The cofactor 4A residues 990-1000(GLY SER VAL VAL ILE VAL GLY ARG ILE ASN LEU) in this entry correspond to residues numbering 1678-1688 of database sequence reference (UNP A8DG50). This peptide is covalently linked to the N-terminus of NS3. C1679S mutation was engineered to prevent disulfide formation. The V1686I and I1687N were engineered to optimize the linker between the cofactor 4A and NS3.

HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS

NS3/4A (E.C.3.4.21.98)/peptide inhibitor complex

HCV, Hepatitis C Virus, NS3, protease, drug resistance, serine protease, chimera protein, fusion protein, HYDROLASE-HYDROLASE INHIBITOR complex

APITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTAAQTFLATCINGVCWTVYHGAGTRTIASPKGPVIQMYTNVDK
DLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPLLCPAGHAVGIFRAAVCT
RGVAKAVDFIPVESLETTMRSP