Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1994 Sep 25;22(19):3966–3976. doi: 10.1093/nar/22.19.3966

RNA tertiary structure of the HIV RRE domain II containing non-Watson-Crick base pairs GG and GA: molecular modeling studies.

S Y Le 1, N Pattabiraman 1, J V Maizel Jr 1
PMCID: PMC308397  PMID: 7937119

Abstract

We have used molecular modeling techniques to model the RNA tertiary structure of the viral RNA element (referred to as domain II of Rev responsive element, RRE) bound by the Rev protein of HIV. In this study, the initial three-dimensional model was built from its established RNA secondary structure, including three non-Watson-Crick G:G, G:A and G:U base pairs. Molecular dynamics (MD) simulations were performed with hydrated or unhydrated sodium ions. Our results indicate that the non-Watson-Crick base pairs in the simulation with unhydrated sodium ions and water are more stable than those with hydrated sodium ions only. The RNA can maintain its compact double helical structure throughout the course of the MD simulations with water and unhydrated sodium ions, although the non-Watson-Crick base pairs and two bulge loops show much more flexibility and conformational distortion than the classical RNA helical region. The distinct distortion of the sugar-phosphate backbone significantly widens the RNA major groove so that the major groove is readily accessible for hydrogen bonding by specific Rev binding. This model emphasizes the importance of specific hydrogen bonding in the stabilization of the three-dimensional structure of the HIV Rev core binding element, not only between the nucleotide bases, but also among the ribose hydroxyls, phosphate anionic oxygens, base oxygens and nitrogens, and bridging water molecules. Moreover, our results suggest that sodium ions play an important role in the formation of base pairs G:G and G:A of the RRE by a manner similar to the arginine of the Rev-RRE complex.

Full text

PDF
3966

Images in this article

3971Image
on p.3971
3971Image
on p.3971
3974Image
on p.3974
3974Image
on p.3974

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arnott S., Hukins D. W., Dover S. D., Fuller W., Hodgson A. R. Structures of synthetic polynucleotides in the A-RNA and A'-RNA conformations: x-ray diffraction analyses of the molecular conformations of polyadenylic acid--polyuridylic acid and polyinosinic acid--polycytidylic acid. J Mol Biol. 1973 Dec 5;81(2):107–122. doi: 10.1016/0022-2836(73)90183-6. [DOI] [PubMed] [Google Scholar]
  2. Bartel D. P., Zapp M. L., Green M. R., Szostak J. W. HIV-1 Rev regulation involves recognition of non-Watson-Crick base pairs in viral RNA. Cell. 1991 Nov 1;67(3):529–536. doi: 10.1016/0092-8674(91)90527-6. [DOI] [PubMed] [Google Scholar]
  3. Battiste J. L., Tan R., Frankel A. D., Williamson J. R. Binding of an HIV Rev peptide to Rev responsive element RNA induces formation of purine-purine base pairs. Biochemistry. 1994 Mar 15;33(10):2741–2747. doi: 10.1021/bi00176a001. [DOI] [PubMed] [Google Scholar]
  4. Dayton E. T., Powell D. M., Dayton A. I. Functional analysis of CAR, the target sequence for the Rev protein of HIV-1. Science. 1989 Dec 22;246(4937):1625–1629. doi: 10.1126/science.2688093. [DOI] [PubMed] [Google Scholar]
  5. Feinberg M. B., Jarrett R. F., Aldovini A., Gallo R. C., Wong-Staal F. HTLV-III expression and production involve complex regulation at the levels of splicing and translation of viral RNA. Cell. 1986 Sep 12;46(6):807–817. doi: 10.1016/0092-8674(86)90062-0. [DOI] [PubMed] [Google Scholar]
  6. Giver L., Bartel D., Zapp M., Pawul A., Green M., Ellington A. D. Selective optimization of the Rev-binding element of HIV-1. Nucleic Acids Res. 1993 Nov 25;21(23):5509–5516. doi: 10.1093/nar/21.23.5509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Heaphy S., Dingwall C., Ernberg I., Gait M. J., Green S. M., Karn J., Lowe A. D., Singh M., Skinner M. A. HIV-1 regulator of virion expression (Rev) protein binds to an RNA stem-loop structure located within the Rev response element region. Cell. 1990 Feb 23;60(4):685–693. doi: 10.1016/0092-8674(90)90671-z. [DOI] [PubMed] [Google Scholar]
  8. Heus H. A., Pardi A. Structural features that give rise to the unusual stability of RNA hairpins containing GNRA loops. Science. 1991 Jul 12;253(5016):191–194. doi: 10.1126/science.1712983. [DOI] [PubMed] [Google Scholar]
  9. Holbrook S. R., Cheong C., Tinoco I., Jr, Kim S. H. Crystal structure of an RNA double helix incorporating a track of non-Watson-Crick base pairs. Nature. 1991 Oct 10;353(6344):579–581. doi: 10.1038/353579a0. [DOI] [PubMed] [Google Scholar]
  10. Holland S. M., Ahmad N., Maitra R. K., Wingfield P., Venkatesan S. Human immunodeficiency virus rev protein recognizes a target sequence in rev-responsive element RNA within the context of RNA secondary structure. J Virol. 1990 Dec;64(12):5966–5975. doi: 10.1128/jvi.64.12.5966-5975.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Huang X. J., Hope T. J., Bond B. L., McDonald D., Grahl K., Parslow T. G. Minimal Rev-response element for type 1 human immunodeficiency virus. J Virol. 1991 Apr;65(4):2131–2134. doi: 10.1128/jvi.65.4.2131-2134.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Iwai S., Pritchard C., Mann D. A., Karn J., Gait M. J. Recognition of the high affinity binding site in rev-response element RNA by the human immunodeficiency virus type-1 rev protein. Nucleic Acids Res. 1992 Dec 25;20(24):6465–6472. doi: 10.1093/nar/20.24.6465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kalnik M. W., Norman D. G., Zagorski M. G., Swann P. F., Patel D. J. Conformational transitions in cytidine bulge-containing deoxytridecanucleotide duplexes: extra cytidine equilibrates between looped out (low temperature) and stacked (elevated temperature) conformations in solution. Biochemistry. 1989 Jan 10;28(1):294–303. doi: 10.1021/bi00427a040. [DOI] [PubMed] [Google Scholar]
  14. Kim S. H., Suddath F. L., Quigley G. J., McPherson A., Sussman J. L., Wang A. H., Seeman N. C., Rich A. Three-dimensional tertiary structure of yeast phenylalanine transfer RNA. Science. 1974 Aug 2;185(4149):435–440. doi: 10.1126/science.185.4149.435. [DOI] [PubMed] [Google Scholar]
  15. Kjems J., Calnan B. J., Frankel A. D., Sharp P. A. Specific binding of a basic peptide from HIV-1 Rev. EMBO J. 1992 Mar;11(3):1119–1129. doi: 10.1002/j.1460-2075.1992.tb05152.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Le S. Y., Malim M. H., Cullen B. R., Maizel J. V. A highly conserved RNA folding region coincident with the Rev response element of primate immunodeficiency viruses. Nucleic Acids Res. 1990 Mar 25;18(6):1613–1623. doi: 10.1093/nar/18.6.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Leclerc F., Cedergren R., Ellington A. D. A three-dimensional model of the Rev-binding element of HIV-1 derived from analyses of aptamers. Nat Struct Biol. 1994 May;1(5):293–300. doi: 10.1038/nsb0594-293. [DOI] [PubMed] [Google Scholar]
  18. Lee W. K., Gao Y., Prohofsky E. W. Structure of hydrated Na+ ions around a region of A- or B-DNA helix. Biopolymers. 1984 Feb;23(2):257–270. doi: 10.1002/bip.360230207. [DOI] [PubMed] [Google Scholar]
  19. Malim M. H., Hauber J., Le S. Y., Maizel J. V., Cullen B. R. The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature. 1989 Mar 16;338(6212):254–257. doi: 10.1038/338254a0. [DOI] [PubMed] [Google Scholar]
  20. Malim M. H., Tiley L. S., McCarn D. F., Rusche J. R., Hauber J., Cullen B. R. HIV-1 structural gene expression requires binding of the Rev trans-activator to its RNA target sequence. Cell. 1990 Feb 23;60(4):675–683. doi: 10.1016/0092-8674(90)90670-a. [DOI] [PubMed] [Google Scholar]
  21. Morden K. M., Gunn B. M., Maskos K. NMR studies of a deoxyribodecanucleotide containing an extrahelical thymidine surrounded by an oligo(dA).oligo(dT) tract. Biochemistry. 1990 Sep 18;29(37):8835–8845. doi: 10.1021/bi00489a047. [DOI] [PubMed] [Google Scholar]
  22. Nikonowicz E. P., Gorenstein D. G. Two-dimensional 1H and 31P NMR spectra and restrained molecular dynamics structure of a mismatched GA decamer oligodeoxyribonucleotide duplex. Biochemistry. 1990 Sep 18;29(37):8845–8858. doi: 10.1021/bi00489a048. [DOI] [PubMed] [Google Scholar]
  23. Nikonowicz E. P., Meadows R. P., Gorenstein D. G. NMR structural refinement of an extrahelical adenosine tridecamer d(CGCAGAATTCGCG)2 via a hybrid relaxation matrix procedure. Biochemistry. 1990 May 1;29(17):4193–4204. doi: 10.1021/bi00469a024. [DOI] [PubMed] [Google Scholar]
  24. Peterson R. D., Bartel D. P., Szostak J. W., Horvath S. J., Feigon J. 1H NMR studies of the high-affinity Rev binding site of the Rev responsive element of HIV-1 mRNA: base pairing in the core binding element. Biochemistry. 1994 May 10;33(18):5357–5366. doi: 10.1021/bi00184a001. [DOI] [PubMed] [Google Scholar]
  25. Prabhakaran M., Harvey S. C., Mao B., McCammon J. A. Molecular dynamics of phenylalanine transfer RNA. J Biomol Struct Dyn. 1983 Oct;1(2):357–369. doi: 10.1080/07391102.1983.10507447. [DOI] [PubMed] [Google Scholar]
  26. Robertus J. D., Ladner J. E., Finch J. T., Rhodes D., Brown R. S., Clark B. F., Klug A. Structure of yeast phenylalanine tRNA at 3 A resolution. Nature. 1974 Aug 16;250(467):546–551. doi: 10.1038/250546a0. [DOI] [PubMed] [Google Scholar]
  27. Rosen M. A., Live D., Patel D. J. Comparative NMR study of A(n)-bulge loops in DNA duplexes: intrahelical stacking of A, A-A, and A-A-A bulge loops. Biochemistry. 1992 Apr 28;31(16):4004–4014. doi: 10.1021/bi00131a016. [DOI] [PubMed] [Google Scholar]
  28. Rosen M. A., Shapiro L., Patel D. J. Solution structure of a trinucleotide A-T-A bulge loop within a DNA duplex. Biochemistry. 1992 Apr 28;31(16):4015–4026. doi: 10.1021/bi00131a017. [DOI] [PubMed] [Google Scholar]
  29. Singh U. C., Weiner S. J., Kollman P. Molecular dynamics simulations of d(C-G-C-G-A) X d(T-C-G-C-G) with and without "hydrated" counterions. Proc Natl Acad Sci U S A. 1985 Feb;82(3):755–759. doi: 10.1073/pnas.82.3.755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sodroski J., Goh W. C., Rosen C., Dayton A., Terwilliger E., Haseltine W. A second post-transcriptional trans-activator gene required for HTLV-III replication. Nature. 1986 May 22;321(6068):412–417. doi: 10.1038/321412a0. [DOI] [PubMed] [Google Scholar]
  31. Varani G., Cheong C., Tinoco I., Jr Structure of an unusually stable RNA hairpin. Biochemistry. 1991 Apr 2;30(13):3280–3289. doi: 10.1021/bi00227a016. [DOI] [PubMed] [Google Scholar]
  32. Weeks K. M., Crothers D. M. RNA recognition by Tat-derived peptides: interaction in the major groove? Cell. 1991 Aug 9;66(3):577–588. doi: 10.1016/0092-8674(81)90020-9. [DOI] [PubMed] [Google Scholar]
  33. White S. A., Nilges M., Huang A., Brünger A. T., Moore P. B. NMR analysis of helix I from the 5S RNA of Escherichia coli. Biochemistry. 1992 Feb 18;31(6):1610–1621. doi: 10.1021/bi00121a005. [DOI] [PubMed] [Google Scholar]
  34. Yao S., Wilson W. D. A molecular mechanics investigation of RNA complexes. I. Ethidium intercalation in an HIV-1 TAR RNA sequence with an unpaired adenosine. J Biomol Struct Dyn. 1992 Oct;10(2):367–387. doi: 10.1080/07391102.1992.10508653. [DOI] [PubMed] [Google Scholar]
  35. Zapp M. L., Stern S., Green M. R. Small molecules that selectively block RNA binding of HIV-1 Rev protein inhibit Rev function and viral production. Cell. 1993 Sep 24;74(6):969–978. doi: 10.1016/0092-8674(93)90720-b. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES