Review of HIV-1 reverse transcriptase three-dimensional structure: Implications for drug design

Summary

Two recent X-ray crystallographic studies have resulted in the three-dimensional structure determination of the reverse transcriptase (RT) enzyme from the human immunodeficiency virus type 1 (HIV-1) [Kohlstaedt et al., Science, 256 (1992) 1783; Jacobo-Molina et al., Proc. Natl. Acad. Sci. USA, 90 (1993) 6320]. This report reviews the structure of the reverse transcriptase heterodimer and provides a detailed description of the folding and topology of the individual subdomains. The interactions of the enzyme with bound template- primer are highlighted. Structure-function relationships have been established and are discussed for several conserved sequence motifs located within the enzyme. Each of these motifs is found to interact significantly with template-primer during the polymerization process. This review integrates the findings of both structure determinations, in particular, to relate these structures to strategies for drug design and development. The structures of both the nucleoside and nonnucleoside inhibitor binding sites are described, and the spatial relationship between the two sites is discussed in light of some novel possibilities for drug development. The first indication of an HIV-1 RT drug-resistant mutation manifested in the p51 subunit is presented. This mutation is located in a region of p51 that is proximal to the nonnucleoside binding pocket. The mechanisms of HIV-1 RT inhibition by both nucleoside and nonnucleoside classes of inhibitors are discussed in relation to the structure of the enzyme. In addition, the implications of the structure for understanding and avoiding the development of resistance of HIV-1 reverse transcriptase to antiviral inhibitors are discussed.

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Nanni, R.G., Ding, J., Jacobo-Molina, A. et al. Review of HIV-1 reverse transcriptase three-dimensional structure: Implications for drug design. Perspectives in Drug Discovery and Design 1, 129–150 (1993). https://doi.org/10.1007/BF02171659

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Key words

  • AIDS
  • Antiviral agents
  • Drug resistance
  • Polymerase structure
  • Protein-nucleic acid interactions
  • Reverse transcriptase inhibitors