TMC278 is a diarylpyrimidine (DAPY) nonnucleoside
reverse transcriptase inhibitor (NNRTI) that is highly effective in treating wild-type and
drug-resistant HIV-1
infections in clinical trials at relatively low doses ( approximately 25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with
TMC278 at 1.8 A resolution, using an RT crystal form engineered by systematic RT mutagenesis. This high-resolution structure reveals that the cyanovinyl group of
TMC278 is positioned in a hydrophobic tunnel connecting the NNRTI-binding pocket to the
nucleic acid-binding cleft. The crystal structures of
TMC278 in complexes with the double mutant K103N/Y181C (2.1 A) and L100I/K103N HIV-1 RTs (2.9 A) demonstrated that
TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/
TMC278 structure, loss of the aromatic ring interaction caused by the Y181C mutation is counterbalanced by interactions between the cyanovinyl group of
TMC278 and the aromatic side chain of Y183, which is facilitated by an approximately 1.5 A shift of the conserved Y(183)MDD motif. In the L100I/K103N RT/
TMC278 structure, the binding mode of
TMC278 is significantly altered so that the
drug conforms to changes in the binding pocket primarily caused by the L100I mutation. The flexible binding pocket acts as a molecular "shrink wrap" that makes a shape complementary to the optimized
TMC278 in wild-type and
drug-resistant forms of HIV-1 RT. The crystal structures provide a better understanding of how the flexibility of an inhibitor can compensate for drug-resistance mutations.