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

Edward Arnold*, Alfredo Jacobo-Molina, Raymond G. Nanni, Roger L. Williams, Xiaode Lu, Jianping Ding, Arthur D. Clark, Anqiang Zhang, Andrea L. Ferris, Patrick Clark, Amnon Hizi, Stephen H. Hughes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 time 1,2. 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.

Original languageEnglish
Pages (from-to)85-89
Number of pages5
JournalNature
Volume357
Issue number6373
DOIs
StatePublished - 1992

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