Overview of sites of resistance mutations.  NRTIs bind at the polymerase active site; NNRTIs bind to a hydrophobic pocket near, but not at, the polymerase active site.  Mutations that give rise to NNRTI resistance cluster around the hydrophobic binding pocket where these compounds bind.  NNRTI resistance mutations can reduce hydrophobic interactions with the drugs (mutations at 181 or 188) (see Nonnucleoside RT Inhibitors Figure 2 and Figure 3), cause a decrease in the size of the pocket that makes the binding of some NNRTIs less favorable (mutations at 190), or generate a hydrogen bond at the pocket entrance, making it more difficult for inhibitors to enter the pocket (K103N) (see Nonnucleoside RT Inhibitors Figure 4).

Some NRTI resistance mutations are in the dNTP binding pocket (for example, M184V/M184I, which confer resistance to 3TC).  However, a number of the mutations that confer resistance to AZT are not part of the dNTP binding pocket.  We believe that at least some of these mutations enhance the ability of the mutant enzyme to bind ATP, which is the pyrophosphate donor for the excision of AZTMP (see Nucleoside RT Inhibitors Figure 4).