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Conserved glycine 33 residue in flexible domain I of hepatitis C virus core protein is critical for virus infectivity

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  • Allan G. N. Angus
  • Antoine Loquet
  • Séamus J. Stack
  • David Dalrymple
  • Derek Gatherer
  • François Penin
  • Arvind H. Patel
<mark>Journal publication date</mark>01/2012
<mark>Journal</mark>Journal of Virology
Issue number2
Number of pages12
Pages (from-to)679-690
Publication StatusPublished
<mark>Original language</mark>English


Hepatitis C virus core protein forms the viral nucleocapsid and plays a critical role in the formation of infectious particles. In this study, we demonstrate that the highly conserved residue G33, located within domain 1 of the core protein, is important for the production of cell culture-infectious virus (HCVcc). Alanine substitution at this position in the JFH1 genome did not alter viral RNA replication but reduced infectivity by ∼2 logs. Virus production by this core mutant could be rescued by compensatory mutations located immediately upstream and downstream of the original G33A mutation. The examination of the helix-loop-helix motif observed in the core protein structure (residues 15 to 41; Protein Data Bank entry 1CWX) indicated that the residues G33 and F24 are in close contact with each other, and that the G33A mutation induces a steric clash with F24. Molecular simulations revealed that the compensatory mutations increase the helix-loop-helix flexibility, allowing rescue of the core active conformation required for efficient virus production. Taken together, these data highlight the plasticity of core domain 1 conformation and illustrate the relationship between its structural tolerance to mutations and virus infectivity.