Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1782127427607068672 |
---|---|
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. |
format | Text |
id | pubmed-1458285 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ennifareric targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT paillartjeanchristophe targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT bodlenneranne targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT walterphilippe targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT weibeljeanmarc targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT aubertinannemarie targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT palepatrick targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT dumasphilippe targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell AT marquetroland targetingthedimerizationinitiationsiteofhiv1rnawithaminoglycosidesfromcrystaltocell |