Steps in the polymerization reaction.  The polymerization reaction can be divided into discreet steps, as shown in the reaction diagram at the bottom of the figure.  There are crystallographic structures that correspond to a number of the states listed in the reaction diagram.  A comparison of these structures shows that HIV-1 RT is a physically flexible enzyme; portions of the enzyme undergo significant movements as it carries out the polymerization reaction.  Much of the movement involves the fingers and thumb of the p66 subunit.  In the unliganded enzyme (a), the thumb (green) is close to the fingers (blue).  The thumb must move away from the fingers to accommodate the nucleic acid substrate (b->c).  In the RT/DNA complex, the end of the primer strand is near the polymerase active site (b).  When the incoming dNTP binds to this complex, the fingers of p66 close down onto the bound dNTP (b->c).  This conformational change is believed to be the slow step in polymerization.  Once the fingers close, the enzyme can carry out the chemical step of polymerization, joining the incoming dNTP to the end of the primer strand, releasing pyrophosphate.  The enzyme translocates one nucleotide along the DNA, and in processive DNA synthesis the polymerization cycle is repeated.  Alternatively, the DNA can dissociate from the DNA (E + DNA).