Conformational stability of hepatitis C virus NS3 protease.
The hepatitis C virus NS3 protease is responsible for the processing of the nonstructural region of viral precursor polyprotein in infected hepatic cells. NS3 has been considered a target for drug discovery for a long time. NS3 is a zinc-dependent serine protease. However, the zinc ion is not involved in the catalytic mechanism, because it is bound far away from the active site. Thus, zinc is essential for the structural integrity of the protein and it is considered to have a structural role. The first thermodynamic study on the conformational equilibrium and stability of NS3 and the effect of zinc on such equilibrium is presented here. In agreement with a previous calorimetric study on the binding of zinc to NS3, the global unfolding heat capacity is dominated by the zinc dissociation step, suggesting that the binding of zinc induces a significant structural rearrangement of the protein. In addition, contrary to other homologous zinc-dependent proteases, the zinc-free NS3 protease is not completely unstructured. It is apparent that the conformational landscape of hepatitis C virus NS3 protease is fairly complex due to its intrinsic plasticity, and to the interactions with its different effectors (zinc and the accessory viral protein NS4A) and their modulation of the population of the different conformational states.
Institute of Biocomputation and Physics of Complex Systems, Universidad de Zaragoza, Zaragoza, Spain. omabian.iacs@aragon.es
Olga
O
Abian
Sonia
S
Vega
Jose Luis
JL
Neira
Adrian
A
Velazquez-Campoy
D002152:Calorimetry, Differential Scanning; D004795:Enzyme Stability; D005453:Fluorescence; D016174:Hepacivirus / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D013696:Temperature; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D017361:Viral Nonstructural Proteins; D015032:Zinc; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases