HIV-1 RNA dimerization initiation site is structurally similar to the ribosomal A site and binds aminoglycoside antibiotics.
Human immunodeficiency virus (HIV) genomic RNA is packaged into virions as a dimer. The first step of dimerization is the formation of a kissing-loop complex at the so-called dimerization initiation site (DIS). We found an unexpected and fortuitous resemblance between the HIV-1 DIS kissing-loop complex and the eubacterial 16 S ribosomal aminoacyl-tRNA site (A site), which is the target of aminoglycoside antibiotics. Similarities exist not only at the primary and secondary structure level but also at the tertiary structure level, as revealed by comparison of the respective DIS and A site crystal structures. Gel shift, inhibition of lead-induced cleavage, and footprinting experiments showed that paromomycin and neomycin specifically bind to the kissing-loop complex formed by the DIS, with an affinity and a geometry similar to that observed for the A site. Modeling of the aminoglycoside-DIS complex allowed us to identify antibiotic modifications likely to increase the affinity and/or the specificity for the DIS. This could be a starting point for designing antiviral drugs against HIV-1 RNA dimerization.
Ennifar
Eric
E
UPR9002-Institut de Biologie Moléculaire et Cellulaire du CNRS, 15, rue René Descartes, F-67084 Strasbourg cedex, France.
Paillart
Jean-Christophe
JC
Marquet
Roland
R
Ehresmann
Bernard
B
Ehresmann
Chantal
C
Dumas
Philippe
P
Walter
Philippe
P
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001665:Binding Sites; D019281:Dimerization; D015497:HIV-1 / Q000378:metabolism*; D008958:Models, Molecular; D009355:Neomycin / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D010303:Paromomycin / Q000494:pharmacology; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012367:RNA, Viral; D012270:Ribosomes / Q000378:metabolism*; D013696:Temperature; D014466:Ultraviolet Rays
D000900:Anti-Bacterial Agents; D012367:RNA, Viral; D010303:Paromomycin; D012313:RNA; D009355:Neomycin