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Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell

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...

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Autores principales: Ennifar, Eric, Paillart, Jean-Christophe, Bodlenner, Anne, Walter, Philippe, Weibel, Jean-Marc, Aubertin, Anne-Marie, Pale, Patrick, Dumas, Philippe, Marquet, Roland
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458285/
https://www.ncbi.nlm.nih.gov/pubmed/16679451
http://dx.doi.org/10.1093/nar/gkl317
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author Ennifar, Eric
Paillart, Jean-Christophe
Bodlenner, Anne
Walter, Philippe
Weibel, Jean-Marc
Aubertin, Anne-Marie
Pale, Patrick
Dumas, Philippe
Marquet, Roland
author_facet Ennifar, Eric
Paillart, Jean-Christophe
Bodlenner, Anne
Walter, Philippe
Weibel, Jean-Marc
Aubertin, Anne-Marie
Pale, Patrick
Dumas, Philippe
Marquet, Roland
author_sort Ennifar, Eric
collection PubMed
description 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.
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spelling pubmed-14582852006-05-12 Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell Ennifar, Eric Paillart, Jean-Christophe Bodlenner, Anne Walter, Philippe Weibel, Jean-Marc Aubertin, Anne-Marie Pale, Patrick Dumas, Philippe Marquet, Roland Nucleic Acids Res 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. Oxford University Press 2006 2006-05-05 /pmc/articles/PMC1458285/ /pubmed/16679451 http://dx.doi.org/10.1093/nar/gkl317 Text en © The Author 2006. Published by Oxford University Press. All rights reserved
spellingShingle Article
Ennifar, Eric
Paillart, Jean-Christophe
Bodlenner, Anne
Walter, Philippe
Weibel, Jean-Marc
Aubertin, Anne-Marie
Pale, Patrick
Dumas, Philippe
Marquet, Roland
Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
title Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
title_full Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
title_fullStr Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
title_full_unstemmed Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
title_short Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
title_sort targeting the dimerization initiation site of hiv-1 rna with aminoglycosides: from crystal to cell
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458285/
https://www.ncbi.nlm.nih.gov/pubmed/16679451
http://dx.doi.org/10.1093/nar/gkl317
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