STRUCTURE OF THE BINDING-SITE FOR NONNUCLEOSIDE INHIBITORS OF THE REVERSE-TRANSCRIPTASE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

The dipyridodiazepinone Nevirapine is a potent and highly specific inh ibitor of the reverse transcriptase (RT) from human immunodeficiency v irus type 1 (HIV-1). It is a member of an important class of nonnucleo side drugs that appear to share part or all of the same binding site o n the enzyme but are susceptible to a variety of spontaneous drug-resi stance mutations. The co-crystal-structure of HIV-1 RT and Nevirapine has been solved previously at 3.5-Angstrom resolution and now is parti ally refined against data extending to 2.9-Angstrom spacing. The drug is bound in a hydrophobic pocket and in contact with some 38 protein a toms from the p66 palm and thumb subdomains. Most, but not all, nonnuc leoside drug-resistance mutations map to residues in close contact wit h Nevirapine. The major effects of these mutations are to introduce st eric clashes with the drug molecule or to remove favorable protein-dru g contacts. Additionally, four residues (Phe-227, Trp-229, Leu-234, an d Tyr-319) in contact with Nevirapine have not been selected as sites of drug-resistance mutations, implying that there may be limitations o n the number and types of resistance mutations that yield viable virus . Strategies of inhibitor design that target interactions with these c onserved residues may yield drugs that are less vulnerable to escape m utations.