title: A 3D structural model and dynamics of hepatitis C virus NS3/4A protease (genotype 4a, strain ED43) suggest conformational instability of the catalytic triad: implications in catalysis and drug resistivity.
abstract: Egypt has the highest prevalence of hepatitis C virus (HCV) infection worldwide with a frequency of 15%. More than 90% of these infections are due to genotype 4, and the subtype 4a (HCV-4a) predominates. Moreover, due to the increased mobility of people, HCV-4a has recently spread to several European countries. The protease domain of the HCV nonstructural protein 3 (NS3) has been targeted for inhibition by several drugs. This approach has had marked success in inhibiting genotype 1 (HCV-1), the predominant genotype in the USA, Europe, and Japan. However, HCV-4a was found to resist inhibition by a number of these drugs, and little progress has been made to understand the structural basis of its drug resistivity. As a step forward, we sequenced the NS3 HCV-4a protease gene (strain ED43) and subsequently built a 3D structural model threaded through a template crystal structure of HCV-1b NS3 protease. The model protease, HCV-4a, shares 83% sequence identity with the template protease, HCV-1b, and has nearly identical rigid structural features. Molecular dynamics simulations predict similar overall dynamics of the two proteases. However, local dynamics and 4D analysis of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-4a NS3 protease. These results suggest that the divergent dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug resistivity seen in HCV-4a.
authors.affiliation: a Department of Physics , College of Arts and Sciences, Southern Illinois University Edwardsville , Edwardsville , IL , 62026-1654 , USA .
authors.forename: Bradley
authors.initials: B
authors.lastname: Rimmert
authors.forename: Salwa
authors.initials: S
authors.lastname: Sabet
authors.forename: Edward
authors.initials: E
authors.lastname: Ackad
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Yousef
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D024882:Drug Resistance, Viral; D005838:Genotype; D006526:Hepatitis C / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases