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Structure of HIV-1 reverse transcriptase/DNA complex at 7 Å resolution showing active site locations

Abstract

AIDS, caused by human immunodeficiency virus (HIV), is one of the world's most serious health problems, with current protocols being inadequate for either prevention or successful long-term treatment. In retroviruses such as HIV, the enzyme reverse tran-scriptase copies the single-stranded RNA genome into double-stranded DNA that is then integrated into the chromosomes of infected cells. Reverse transcriptase is the target of the most widely used treatments for AIDS, 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddl), but resistant strains of HIV-1 arise in patients after a relatively short time1,2. There are several non-nucleoside inhibitors of HIV-1 reverse transcriptase3–6, but resistance to such agents also develops rapidly7. We report here the structure at 7 Å resolution of a ternary complex of the HIV-1 reverse transcriptase heterodimer, a monoclonal antibody Fab fragment8, and a duplex DNA template-primer. The double-stranded DNA binds in a groove on the surface of the enzyme. The electron density near one end of the DNA matches well with the known structure of the HIV-1 reverse transcriptase RNase H domain12. At the opposite end of the DNA, a mercurated derivative of UTP has been localized by difference Fourier methods, allowing tentative identification of the polymerase nucleoside triphosphate binding site. We also determined the structure of the reverse transcriptase/Fab complex in the absence of template-primer to compare the bound and free forms of the enzyme. The presence of DNA correlates with movement of protein electron density in the vicinity of the putative template-primer binding groove. These results have important implications for developing improved inhibitors of reverse transcriptase for the treatment of AIDS.

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Arnold, E., Jacobo-Molina, A., Nanni, R. et al. Structure of HIV-1 reverse transcriptase/DNA complex at 7 Å resolution showing active site locations. Nature 357, 85–89 (1992). https://doi.org/10.1038/357085a0

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