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PDBsum entry 2fd0
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References listed in PDB file
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Key reference
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Title
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Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.
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Authors
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E.Ennifar,
J.C.Paillart,
A.Bodlenner,
P.Walter,
J.M.Weibel,
A.M.Aubertin,
P.Pale,
P.Dumas,
R.Marquet.
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Ref.
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Nucleic Acids Res, 2006,
34,
2328-2339.
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PubMed id
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Abstract
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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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Headers
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