Publications
2006
Ennifar E, Paillart J C, Bodlenner A, Walter P, Weibel J M, Aubertin A M, Pale P, Dumas P, Marquet R
Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell Journal Article
In: Nucleic Acids Research, vol. 34, no. 8, pp. 2328-39, 2006.
Abstract | Links | BibTeX | Tags: Aminoglycosides/*chemistry Anti-HIV Agents/*chemistry Binding Sites Cell Line Crystallography, ENNIFAR, MARQUET, Molecular RNA, Non-U.S. Gov't Virion/chemistry, PAILLART, Unité ARN, Viral/*chemistry Research Support, X-Ray Dimerization Drug Delivery Systems HIV-1/*genetics Humans Models
@article{Ennifar2006,
title = {Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell},
author = {E Ennifar and J C Paillart and A Bodlenner and P Walter and J M Weibel and A M Aubertin and P Pale and P Dumas and R Marquet},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16679451},
doi = {10.1093/nar/gkl317 },
year = {2006},
date = {2006-01-01},
journal = {Nucleic Acids Research},
volume = {34},
number = {8},
pages = {2328-39},
abstract = {The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.},
keywords = {Aminoglycosides/*chemistry Anti-HIV Agents/*chemistry Binding Sites Cell Line Crystallography, ENNIFAR, MARQUET, Molecular RNA, Non-U.S. Gov't Virion/chemistry, PAILLART, Unité ARN, Viral/*chemistry Research Support, X-Ray Dimerization Drug Delivery Systems HIV-1/*genetics Humans Models},
pubstate = {published},
tppubtype = {article}
}
The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.