Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell
Open Access
- 1 January 2006
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 34 (8), 2328-2339
- https://doi.org/10.1093/nar/gkl317
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
This publication has 40 references indexed in Scilit:
- Dimerization of retroviral RNA genomes: an inseparable pairNature Reviews Microbiology, 2004
- Impact of Human Immunodeficiency Virus Type 1 RNA Dimerization on Viral Infectivity and of Stem-Loop B on RNA Dimerization and Reverse Transcription and Dissociation of Dimerization from PackagingJournal of Virology, 2000
- A dual role of the putative RNA dimerization initiation site of human immunodeficiency virus type 1 in genomic RNA packaging and proviral DNA synthesisJournal of Virology, 1996
- Role of the DIS hairpin in replication of human immunodeficiency virus type 1Journal of Virology, 1996
- A loop-loop "kissing" complex is the essential part of the dimer linkage of genomic HIV-1 RNA.Proceedings of the National Academy of Sciences, 1996
- Dimerization of retroviral genomic RNAs: structural and functional implicationsBiochimie, 1996
- Dimerization of HIV-1Lai RNA at Low Ionic StrengthPublished by Elsevier ,1995
- A 19-Nucleotide Sequence Upstream of the 5' Major Splice Donor Is Part of the Dimerization Domain of Human Immunodeficiency Virus 1 Genomic RNABiochemistry, 1994
- Identification of the primary site of the human immunodeficiency virus type 1 RNA dimerization in vitro.Proceedings of the National Academy of Sciences, 1994
- RD-114, baboon, and woolly monkey viral RNAs compared in size and structureCell, 1976