Interactions of conformationally biased north and south 2'-fluoro-2',3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase

L. Mu, S. G. Sarafianos, M. C. Nicklaus, P. Russ, M. A. Siddiqui, Jr Ford, H. Mitsuya, R. Le, E. Kodama, C. Meier, T. Knispel, L. Anderson, Jr J. Barchi, V. E. Marquez

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27 Citations (Scopus)

Abstract

Molecular dynamics simulations of a ternary complex of HIV-1 reverse transcriptase (RT), double-stranded DNA, and bound dideoxynucleoside-5'-triphosphate (RT-DNA-ddNTP), utilizing the ddNTPs ddATP, βFddATP, and αFddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP > βFddATP > αFddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, αFddATP, which in solution prefers almost exclusively a north conformation, was predicted to be the most potent inhibitor. However, Tyr115, which appears to function as a steric gate to preclude the binding of ribonucleoside 5'-triphosphates, prevents the effective binding of αFddATP in its preferred north conformation. The south-biased βFddATP, while able to bind to RT without hindrance by Tyr115, has to pay a high energy penalty to be flipped to the active north conformation at the polymerase site. Finally, the more flexible and less conformationally biased ddATP is able to switch to a north conformation at the RT site with a smaller energy penalty than βFddATP. These results highlight the opposite conformational preferences of HIV-1 RT for αFddATP and βFddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme.

Original languageEnglish
Pages (from-to)11205-11215
Number of pages11
JournalBiochemistry
Volume39
Issue number37
DOIs
Publication statusPublished - 2000 Sep 19
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Mu, L., Sarafianos, S. G., Nicklaus, M. C., Russ, P., Siddiqui, M. A., Ford, J., Mitsuya, H., Le, R., Kodama, E., Meier, C., Knispel, T., Anderson, L., Barchi, J. J., & Marquez, V. E. (2000). Interactions of conformationally biased north and south 2'-fluoro-2',3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase. Biochemistry, 39(37), 11205-11215. https://doi.org/10.1021/bi001090n