Structures of HIV-1 RT–DNA complexes before and after incorporation of the anti-AIDS drug tenofovir
- 25 April 2004
- journal article
- research article
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 11 (5) , 469-474
- https://doi.org/10.1038/nsmb760
Abstract
Tenofovir, also known as PMPA, R-9-(2-(phosphonomethoxypropyl)adenine, is a nucleotide reverse transcriptase (RT) inhibitor. We have determined the crystal structures of two related complexes of HIV-1 RT with template primer and tenofovir: (i) a ternary complex at a resolution of 3.0 Å of RT crosslinked to a dideoxy-terminated DNA with tenofovir-diphosphate bound as the incoming substrate; and (ii) a RT–DNA complex at a resolution of 3.1 Å with tenofovir at the 3′ primer terminus. The tenofovir nucleotide in the tenofovir-terminated structure seems to adopt multiple conformations. Some nucleoside reverse transcriptase inhibitors, including 3TC and AZT, have elements ('handles') that project beyond the corresponding elements on normal dNTPs (the 'substrate envelope'). HIV-1 RT resistance mechanisms to AZT and 3TC take advantage of these handles; tenofovir's structure lacks handles that could protrude through the substrate envelope to cause resistance.Keywords
This publication has 34 references indexed in Scilit:
- Trapping HIV-1 Reverse Transcriptase Before and After Translocation on DNAJournal of Biological Chemistry, 2003
- Nucleoside Analog Resistance Caused by Insertions in the Fingers of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Involves ATP-Mediated ExcisionJournal of Virology, 2002
- Phenotypic Susceptibilities to Tenofovir in a Large Panel of Clinically Derived Human Immunodeficiency Virus Type 1 IsolatesAntimicrobial Agents and Chemotherapy, 2002
- The M184V Mutation Reduces the Selective Excision of Zidovudine 5′-Monophosphate (AZTMP) by the Reverse Transcriptase of Human Immunodeficiency Virus Type 1Journal of Virology, 2002
- YADD Mutants of Human Immunodeficiency Virus Type 1 and Moloney Murine Leukemia Virus Reverse Transcriptase Are Resistant to Lamivudine Triphosphate (3TCTP) In VitroJournal of Virology, 2001
- The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase 1 1Edited by A. R. FershtJournal of Molecular Biology, 2000
- Structure and functional implications of the polymerase active site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody fab fragment at 2.8 Å resolutionJournal of Molecular Biology, 1998
- [20] Processing of X-ray diffraction data collected in oscillation modePublished by Elsevier ,1997
- Improved Strategies for Postoligomerization Synthesis of Oligodeoxynucleotides Bearing Structurally Defined Adducts at the N2 Position of DeoxyguanosineChemical Research in Toxicology, 1996
- Kinetic mechanism of DNA polymerase I(Klenow fragment): identification of a second conformational change and evaluation of the internal equilibrium constantBiochemistry, 1991