Nucleic Acids Research Advance Access published online on October 16, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm856
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
RNA |
Aminoglycoside binding to the HIV-1 RNA dimerization initiation site: thermodynamics and effect on the kissing-loop to duplex conversion
1Architecture et Réactivité des ARN, UPR 9002 CNRS, Université Louis Pasteur, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg and 2Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/Université Louis Pasteur, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France
* To whom correspondence should be addressed. Tel: +33 3 88 41 70 01; Fax: +33 3 88 60 22 18; Email: e.ennifar{at}ibmc.u-strasbg.fr
Received August 27, 2007. Revised September 26, 2007. Accepted September 26, 2007.
Owing to a striking, and most likely fortuitous, structural and sequence similarity with the bacterial 16 S ribosomal A site, the RNA kissing-loop complex formed by the HIV-1 genomic RNA dimerization initiation site (DIS) specifically binds 4,5-disubstituted 2-deoxystreptamine (2-DOS) aminoglycoside antibiotics. We used chemical probing, molecular modeling, isothermal titration calorimetry (ITC) and UV melting to investigate aminoglycoside binding to the DIS loop–loop complex. We showed that apramycin, an aminoglycoside containing a bicyclic moiety, also binds the DIS, but in a different way than 4,5-disubstituted 2-DOS aminoglycosides. The determination of thermodynamic parameters for various aminoglycosides revealed the role of the different rings in the drug–RNA interaction. Surprisingly, we found that the affinity of lividomycin and neomycin for the DIS (Kd 
30 nM) is significantly higher than that obtained in the same experimental conditions for their natural target, the bacterial A site (Kd 1.6 µM). In good agreement with their respective affinity, aminoglycoside increase the melting temperature of the loop–loop interaction and also block the conversion from kissing-loop complex to extended duplex. Taken together, our data might be useful for selecting new molecules with improved specificity and affinity toward the HIV-1 DIS RNA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. Olieric, U. Rieder, K. Lang, A. Serganov, C. Schulze-Briese, R. Micura, P. Dumas, and E. Ennifar A fast selenium derivatization strategy for crystallization and phasing of RNA structures RNA, April 1, 2009; 15(4): 707 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Xiao, H. Zhang, and P. Guo Novel mechanism of hexamer ring assembly in protein/RNA interactions revealed by single molecule imaging Nucleic Acids Res., November 1, 2008; 36(20): 6620 - 6632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Pallan, C. Kreutz, S. Bosio, R. Micura, and M. Egli Effects of N2,N2 -dimethylguanosine on RNA structure and stability: Crystal structure of an RNA duplex with tandem m2 2G:A pairs RNA, October 1, 2008; 14(10): 2125 - 2135. [Abstract] [Full Text] [PDF]
|
|