Background: HCV-linked pathologies represent worldwide health threats. Over
the years, an enormous number of independent studies have been devoted to the understanding
of the molecular bases of HCV infection. A significant amount of these investigations has
been focused on the structural characterization of the virus proteins with the aim of developing
structure-based innovative therapeutic approaches. An analysis of the current Protein Data
Bank content unravels that the structural biology of the virus has hitherto covered a large
fraction of the HCV proteins (75%).
Objective: The present review recapitulates the state-of-the-art of structural characterizations
of HCV individual proteins with a specific focus on their structural versatility/flexibility.
Results: This survey indicates there is accumulating evidence that structural flexibility is a
common feature among HCV proteins. This versatility can be detected at different structural
level i.e. occurrence of alternative oligomeric states and/or of local and global flexibility.
Somewhat surprisingly, some disordered or highly flexible regions of HCV proteins, such as
the core and the antigenic fragment 412-423 of E2, present highly conserved sequences
among the virus genotypes. The overall versatility of HCV proteins plays an important role in
host protein recognition, drug resistance mechanisms, and virus escape from the host immunogenic
system. Of particular relevance is the emerging idea that HCV uses local structural
flexibility as an alternative tool to sequence variability to evade the immune response of the
Conclusion: We believe that concepts emerged from this survey will be important for the
development of anti-HCV vaccines that are eagerly needed.