title: HIV-1 RNA dimerization initiation site is structurally similar to the ribosomal A site and binds aminoglycoside antibiotics.
abstract: 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.
authors.affiliation: UPR9002-Institut de Biologie Moléculaire et Cellulaire du CNRS, 15, rue René Descartes, F-67084 Strasbourg cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Ennifar
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Paillart
authors.forename: Roland
authors.initials: R
authors.lastname: Marquet
authors.forename: Bernard
authors.initials: B
authors.lastname: Ehresmann
authors.forename: Chantal
authors.initials: C
authors.lastname: Ehresmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Dumas
authors.forename: Philippe
authors.initials: P
authors.lastname: Walter
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D012367:RNA, Viral; D010303:Paromomycin; D012313:RNA; D009355:Neomycin