12 The Structure of HIV-1 Reverse Transcriptase

Abstract

Although reverse transcriptase (RT) was first described in Rous sarcoma virus (RSV) (Baltimore 1970; Temin and Mitzutani 1970), and RSV RT and other RTs from DNA tumor viruses have been studied for many years (Weiss et al. 1982), the recent intense interest in human immunodeficiency virus type 1 (HIV-1) has led to the crystal structure of HIV RT being solved first. HIV RT is the target of 3′-azidodeoxy-thymidine (AZT) and dideoxyinosine (ddI), which are anti-AIDS drugs that function by terminating the DNA during its synthesis (Mitsuya et al. 1990). In addition, a class of nonnucleotide inhibitors of RT also show potential to be less toxic (Merluzzi et al. 1990; Pauwels et al. 1990). The effectiveness of all current compounds in the treatment of AIDS is limited by the toxicity of nucleotide analogs and by mutations in the RT that render it insensitive to both classes of these inhibitors (Larder and Kemp 1989; Shih et al. 1991; St. Clair et al. 1991). Because the structure of HIV RT is expected to facilitate the design of new inhibitors that might prove to be effective in the control of AIDS, many laboratories have attempted with varying degrees of success to grow crystals of RT suitable for high-resolution structural analysis (Lowe et al. 1988; Unge et al. 1990; Jacobo-Molina et al. 1991; Lloyd et al. 1991).

Recently, a 3.5-Å-resolution crystal structure of RT complexed with a nonnucleotide inhibitor derived from cocrystals that diffract to 3.1-Å resolution has been reported (Kohlstaedt et al. 1992). Additionally,...