Figure 4.  Mechanism of K103N resistance.  Many of the mutations that give rise to NNRTI resistance are in the amino acids that form the binding pocket.  The mutations alter the interaction(s) of the NNRTI and the binding pocket.  However, the K103N mutation, which causes resistance to a wide range of NNRTIs, has a different mechanism.  Position 103 is not part of the hydrophobic NNRTI binding pocket; however, 103 is near the entrance to the pocket.  The K103N mutation does not alter the structure of the complex between RT and NNRTIs (not shown).  Rather, K103N creates a hydrogen bond in unliganded RT; this additional hydrogen bond (N103 to Y188) helps keep the entrance to the pocket closed, making it more difficult for NNRTIs to enter the pocket.  The two figures show the region around the entrance to the NNRTI binding pocket for wild-type RT (left) and the K103N mutant (right).  In the K103N mutant, there is a direct interaction (3.3 angstroms) between the OH of Y188 and the NH2 of N103 (shown as a dotted line).