MECHANISM OF INHIBITION OF HIV-1 REVERSE-TRANSCRIPTASE BY NONNUCLEOSIDE INHIBITORS

The structure of unliganded HIV-1 reverse transcriptase has been deter mined at 2.35 Angstrom resolution and refined to an R-factor of 0.219 (for all data) with good stereochemistry. The unliganded structure was produced by soaking out a weak binding non-nucleoside inhibitor, HEPT , from pregrown crystals. Comparison with the structures of four diffe rent RT and non-nucleoside inhibitor complexes reveals that only minor domain rearrangements occur, but there is a significant repositioning of a three-stranded beta-sheet in the p66 subunit (containing the cat alytic aspartic acid residues 110, 185 and 186) with respect to the re st of the polymerase site. This suggests that NNIs inhibit RT by locki ng the polymerase active site in an inactive conformation, reminiscent of the conformation observed in the inactive p51 subunit.