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

Nature. 1992 May 7;357(6373):85-9. doi: 10.1038/357085a0.


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 transcriptase 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 (ddI), but resistant strains of HIV-1 arise in patients after a relatively short time. There are several nonnucleoside inhibitors of HIV-1 reverse transcriptase, but resistance to such agents also develops rapidly. We report here the structure at 7 A resolution of a ternary complex of the HIV-1 reverse transcriptase heterodimer, a monoclonal antibody Fab fragment, 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 domain. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Binding Sites
  • Crystallization
  • DNA / metabolism
  • DNA-Binding Proteins / chemistry*
  • HIV Reverse Transcriptase
  • HIV-1 / enzymology*
  • Immunoglobulin Fab Fragments
  • Methylmercury Compounds
  • Models, Molecular
  • Molecular Sequence Data
  • Organomercury Compounds
  • Protein Conformation
  • RNA-Directed DNA Polymerase / chemistry*
  • Structure-Activity Relationship
  • Uridine Triphosphate / analogs & derivatives
  • X-Ray Diffraction


  • DNA-Binding Proteins
  • Immunoglobulin Fab Fragments
  • Methylmercury Compounds
  • Organomercury Compounds
  • tetrakis(acetoxymercuri)methane
  • 5'-mercuriuridine triphosphate
  • DNA
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Uridine Triphosphate