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Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Nonnucleoside Inhibitors
Open accessAbstract
The mechanism of inhibition of HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues. Pre-steady-state kinetic analysis was used to establish the mechanism of inhibition by these noncompetitive inhibitors. Analysis of the pre-steady-state burst of DNA polymerization indicated that inhibitors blocked the chemical reaction, but did not interfere with nucleotide binding or the nucleotide-induced conformational change. Rather, in the presence of saturating concentrations of the inhibitors, the nucleoside triphosphate bound tightly ( K d , 100 nM), but nonproductively. The data suggest that an inhibitor combining the functionalities of a nonnucleoside inhibitor and a nucleotide analog could bind very tightly and specifically to reverse transcriptase and could be effective in the treatment of AIDS.
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Cites
Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor
Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P. A., & Steitz, T. A. (1992) · Science · doi:10.1126/science.1377403 · Cited by 1,914
CONFORMATIONAL COUPLING IN DNA POLYMERASE FIDELITY
Johnson, K. A. (1993) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.62.070193.003345 · Cited by 560
Self-citation
Cited by
Young, S. D., Britcher, S. F., Tran, L. O., Payne, L. S., Lumma, W. C., Lyle, T. A., Huff, J. R., Anderson, P. S., Olsen, D. B., & Carroll, S. S. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.12.2602 · Cited by 482
de Béthune, M.-P. (2010) · Antiviral Research · doi:10.1016/j.antiviral.2009.09.008 · Cited by 401
Brautigam, C. A., & Steitz, T. A. (1998) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(98)80010-9 · Cited by 377
An open and closed case for all polymerases
Doublié, S., Sawaya, M. R., & Ellenberger, T. (1999) · Structure · doi:10.1016/s0969-2126(99)80017-3 · Cited by 314
Arnold, J. J., & Cameron, C. E. (2004) · Biochemistry · doi:10.1021/bi035212y · Cited by 178
Metadata
- Authors
- Spence, R. A., Kati, W. M., Anderson, K. S., & Johnson, K. A.
- Venue
- Science
- Published
- 1995-02-17
- Volume
- 267
- Issue
- 5200
- Pages
- 988-993
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2084702672
- Cited by
- 522
- References
- 2
- FWCI
- 18.51
- Type
- journal article
- Language
- en
- Open access
- green
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- Spence, R. A., Kati, W. M., Anderson, K. S., & Johnson, K. A. (1995). Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Nonnucleoside Inhibitors. Science. https://doi.org/10.1126/science.7532321
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