NS3 protease from hepatitis C virus: biophysical studies on an intrinsically disordered protein domain

Int J Mol Sci. 2013 Jun 26;14(7):13282-306. doi: 10.3390/ijms140713282.


The nonstructural protein 3 (NS3) from the hepatitis C virus (HCV) is responsible for processing the non-structural region of the viral precursor polyprotein in infected hepatic cells. NS3 protease activity, located at the N-terminal domain, is a zinc-dependent serine protease. A zinc ion, required for the hydrolytic activity, has been considered as a structural metal ion essential for the structural integrity of the protein. In addition, NS3 interacts with another cofactor, NS4A, an accessory viral protein that induces a conformational change enhancing the hydrolytic activity. Biophysical studies on the isolated protease domain, whose behavior is similar to that of the full-length protein (e.g., catalytic activity, allosteric mechanism and susceptibility to inhibitors), suggest that a considerable global conformational change in the protein is coupled to zinc binding. Zinc binding to NS3 protease can be considered as a folding event, an extreme case of induced-fit binding. Therefore, NS3 protease is an intrinsically (partially) disordered protein with a complex conformational landscape due to its inherent plasticity and to the interaction with its different effectors. Here we summarize the results from a detailed biophysical characterization of this enzyme and present new experimental data.

Publication types

  • Review

MeSH terms

  • Hepacivirus / enzymology*
  • Humans
  • Protein Folding
  • Protein Structure, Tertiary
  • Viral Nonstructural Proteins* / chemistry
  • Viral Nonstructural Proteins* / metabolism
  • Zinc / chemistry
  • Zinc / metabolism


  • NS3 protein, hepatitis C virus
  • NS4 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • Zinc