Structural characterization of the Hepatitis C Virus NS3 protease from genotype 3a: the basis of the genotype 1b vs. 3a inhibitor potency shift.
The first structural characterization of the genotype 3a Hepatitis C Virus NS3 protease is reported, providing insight into the differential susceptibility of 1b and 3a proteases to certain inhibitors. Interaction of the 3a NS3 protease with a P2-P4 macrocyclic and a linear phenethylamide inhibitor was investigated. In addition, the effect of the NS4A cofactor binding on the conformation of the protease was analyzed. Complexation of NS3 with the phenethylamide inhibitor significantly stabilizes the protease but binding does not involve residues 168 and 123, two key amino acids underlying the different inhibition of genotype 1b vs. 3a proteases by P2-P4 macrocycles. Therefore, we studied the dynamic behavior of these two residues in the phenethylamide complex, serving as a model of the situation in the apo 3a protein, in order to explore the structural basis of the inhibition potency shift between the proteases of the genotypes 1b and 3a.
Gallo
Mariana
M
Department of Chemical Science and Technology University of Rome Tor Vergata, Italy.
Bottomley
Matthew James
MJ
Pennestri
Matteo
M
Eliseo
Tommaso
T
Paci
Maurizio
M
Koch
Uwe
U
Bazzo
Renzo
R
Summa
Vincenzo
V
Carfì
Andrea
A
Cicero
Daniel O
DO
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D020349:Surface Plasmon Resonance; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus