Journal
PROTEIN SCIENCE
Volume 25, Issue 1, Pages 46-55Publisher
WILEY
DOI: 10.1002/pro.2776
Keywords
reverse transcriptase; HIV; DNA aptamer; 2 '-O-methylcytidine; p66/p51; SELEX
Categories
Funding
- NIH [P50 GM103368, R37 AI027690]
- Collaborative Development Grant Program [P50 GM103368]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R37AI027690] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM103368, R01GM116645, P41GM103485] Funding Source: NIH RePORTER
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The development of a modified DNA aptamer that binds HIV-1 reverse transcriptase (RT) with ultra-high affinity has enabled the X-ray structure determination of an HIV-1 RT-DNA complex to 2.3 angstrom resolution without the need for an antibody Fab fragment or RT-DNA cross-linking. The 38-mer hairpin-DNA aptamer has a 15 base-pair duplex, a three-deoxythymidine hairpin loop, and a five-nucleotide 5'-overhang. The aptamer binds RT in a template-primer configuration with the 3'-end positioned at the polymerase active site and has 2'-O-methyl modifications at the second and fourth duplex template nucleotides that interact with the p66 fingers and palm subdomains. This structure represents the highest resolution RT-nucleic acid structure to date. The RT-aptamer complex is catalytically active and can serve as a platform for studying fundamental RT mechanisms and for development of anti-HIV inhibitors through fragment screening and other approaches. Additionally, the structure allows for a detailed look at a unique aptamer design and provides the molecular basis for its remarkably high affinity for RT.
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