A schematic of the reaction cycle of guide strand-mediated mRNA cleavage procession . Conformer I: single-stranded siRNA binding in the Argonaute as a template strand with its 3' end associated with the binding cleft in PAZ domain. Conformer II: mRNA strand enters and forms Watson-Crick base pair with the template siRNA strand. Conformer III: the 3' end of siRNA strand shifts to bind to N-terminal domain. Base-pairing between the two strands is completed and mRNA strand is ready for cleavage. Conformer IV: the cleaved mRNA strand is loosely paired with template strand and is ready to dissociate from the protein. Transition I to II corresponds to the mRNA nucleation step, transition II to III corresponds to propagation and adjustment, transition III to IV is the cleavage step and transition IV to I is the product release step.