A model for de novo RNA synthesis at the hepacivirus NS5B active site. A: The polymerase is represented schematically to illustrate key points in the reaction mechanism. B: The RNA template is represented as clear blue squares. NTP are as red squares, the allosteric GTP is represented as a dark blue square, and the bound GTP as a green blue square. C: Binding of the first NTP in the active site. D: The initiation reaction is presented with a yellow lightening. Upon incorporation of the third NTP, the template and the neo synthesized RNA slide to the cavity pushing the GTP towards the flap. E: Intermediate position where the flap, GTP and RNA template are stacked. F: Opening of the flap and release of GTP. G: The polymerase shifts to the elongation mode; the thumb moves to fully open the cavity, and the elongation resumes.