Abstract
We report the structure of HIV-1 reverse transcriptase (RT) complexed with the nonnucleoside inhibitor TIBO R 86183 at 3.0 Å resolution. Comparing this structure with those of complexes of HIV-1 RT/α-APA R 95845 and HIV-1 RT/nevirapine provides a basis for understanding the nature of nonnucleoside inhibitor binding, the structure of the binding site and the interactions between the bound inhibitors and surrounding amino acid residues as well as for understanding mechanisms of inhibition by and resistance to nonnucleoside inhibitors. All three inhibitors considered assume a similar butterfly-like shape and bind to HIV-1 RT in a very similar way. Important differences occur in the conformation of amino acid residues that form the binding pocket.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Larder, B.A. Inhibitors of HIV reverse transcriptase as antiviral agents and drug resistance. In Reverse Transcriptase. (eds. Skalka, A.M. & Goff, S.R), 205–222, (Cold Spring Harbor Laboratory Press, Plainview, New York; 1993).
Pauwels, R. et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343, 470–474(1990).
Merluzzi, V.J. et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250, 1411–1413 (1990).
Goldman, M.E. et al. Pyridinone derivatives: specific human immunodeticiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc. natn. Acad. Sci. U.S.A. 88, 6863–6867 (1991).
Pauwels, R. et al. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of a-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc. natn. Acad. Sci. U.S.A. 90, 1711–1715 (1993).
Romero, D.L. et al. Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc. natn. Acad. Sci. U.S.A. 88, 8806–8810 (1991).
Young, S.D. Non-nucleoside inhibitors of HIV-1 reverse transcriptase. Persp. Drug Discov. Des 1, 181–192 (1993).
De Clercq, E. HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Med. Res. Rev. 13, 229–258 (1993).
Tantillo, C. et al. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase: implications for mechanisms of drug inhibition and resistance. J. molec Biol. 243, 369–387 (1994).
Frank, K.B., Noll, G.J., Connell, E.V. & Sim, I.S. Kinetics of interaction of HIV-1 RT with the antiviral TIBO R82150. J. biol. Chem. 266, 14232–14236 (1991).
White, E.L. et al. A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates. Antiviral Res. 16, 257–266 (1991).
Wu, J.C. et al. A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. Biochemistry 30, 2022–2026 (1991).
Condra, J.H. et al. Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob. Agents Chemother. 36, 1441–1446 (1992).
Althaus, I.W. et al. Steady-state kinetic studies with the nonnucleoside HIV-1 reverse transcriptase inhibitor U-87201E J. biol. Chem. 268, 6119–6124 (1993).
Pauwels, R. et al. New tetrahydroimidazo [4,5,1-j k] [1,4]-benzodiazepin-2 (1-H)-one -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2′,3′ -dideoxynucleoside analogs. Antimicrob. Agents Chemother. 38, 2863–2870. (1995).
Kohlstaedt, L.A., Wang, J., Friedman, J.M., Rice, P.A. & Steitz, T.A. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783–1790 (1992).
Smerdon, S.J. et al. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc natn. Acad. Sci. U.S.A. 91, 3911–3915 (1994).
Ding, J. et al. Structure of HIV-1 reverse transcriptase in a complex with the nonnucleoside inhibitor α-APA R 95845 at 2.8 Å resolution. Structure 3, 365–379 (1995).
Arnold, E., Ding, J., Hughes, S.H. & Hostomsky, Z. Structures of DNA and RNA polymerases and their interactions with nucleic acid substrates. Curr. Opin. in struct. Biol. 5, 27–38 (1995).
Jacobo-Molina, A. et al. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc. natn. Acad. Sci. U.S.A. 90, 6320–6324 (1993).
Jager, J., Smerdon, S., Wang, J., Boisvert, D.C. & Steitz, T.A. Comparison of three different crystal forms shows HIV-1 reverse transcriptase displays an internal swivel motion. Structure 2, 869–876 (1994).
Rodgers, D.W. et al. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc. natn. Acad. Sci. U.S.A. 22, 1222–1226 (1995).
Nanni, R.G., Ding, J., Jacobo-Molina, A., Hughes, S.H. & Arnold, E. Review of HIV-1 reverse transcriptase three-dimensional structure: implications for drug design. Perspect. in Drug Discov. and Des. 1, 129–150 (1993).
Kleywegt, G.J. & Jones, T.A., Detection, delineation, measurement and display of cavities in macromolecular structures. Acta Crystallogr. D50, 178–185 (1994).
Jacques, P.S., Wohrl, B.M., Ottmann, M., Darlix, J.L. & Le Grice, S.F.J. Mutating the ‘primer grip’ of p66 HIV-1 reverse transcriptase implicates tryptophan-229 in template-primer utilization. J. biol. Chem. 269, 26472–26478 (1994).
Spence, R.A., Kati, W.M., Anderson, K.S. & Johnson, K.A. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 267, 988–993 (1995).
De Clercq, E. HIV resistance to reverse transcriptase inhibitors. Biochem. Pharmacol. 47, 155–169 (1994).
Wlodawer, A. & Erickson, J.W. Structure-based inhibitors of HIV-1 protease. A. Rev. Biochem. 62, 543–585 (1993).
Lam, P.Y.S. et al. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 263, 380–384 (1994).
Dorsey, B.D. et al. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J. med. Chem. 37, 3443–3451 (1994).
Carson, M. Ribbon models of macromolecules. J. molec. Graphics 5, 103–106 (1987).
Ren et al. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nature struct. Biology 2, 293–302 (1995).
Esnouf, R. et al. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nature struct. Biology 2, 303–308 (1995).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ding, J., Das, K., Moereels, H. et al. Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat Struct Mol Biol 2, 407–415 (1995). https://doi.org/10.1038/nsb0595-407
Issue Date:
DOI: https://doi.org/10.1038/nsb0595-407
This article is cited by
-
Comparative docking and CoMFA analysis of curcumine derivatives as HIV-1 integrase inhibitors
Molecular Diversity (2011)
-
Synthesis and anti-hepatitis B activity of new substituted uracil and thiouracil glycosides
Archives of Pharmacal Research (2010)
-
Synthesis and Crystal Structure Studies of Novel Bioactive Heterocycle: 7-Chloro-5-Cyclopropyl-9-Methyl-10-(2-Piperidin-1-yl-Ethyl)-5,10-Dihydro-4,5,6,10-Tetraaza-Dibenzo[a, d] Cyclohepten-11-One
Journal of Chemical Crystallography (2009)
-
PostDock: A novel visualization tool for the analysis of molecular docking
Computing and Visualization in Science (2009)
