A structure-based approach for targeting the HIV-1 genomic RNA dimerization initiation site.
Dimerization of the genomic RNA is an important step of the HIV-1 replication cycle. The Dimerization Initiation Site (DIS) promotes dimerization of the viral genome by forming a loop-loop complex between two DIS hairpins. Crystal structures of the DIS loop-loop complex revealed an unexpected and strong similitude with the bacterial 16S ribosomal aminoacyl-tRNA site (A site), which is the target of aminoglycoside antibiotics. As a consequence of these structural and sequence similarities, the HIV-1 DIS also binds some aminoglycosides, not only in vitro, but also ex vivo, in lymphoid cells and in viral particles. Crystal structures of the DIS loop-loop in complex with several aminoglycoside antibiotics provide a detailed-view of the DIS/drug interaction and reveal some hints about possible modifications to increase the drug affinity and/or specificity.
Ennifar
Eric
E
Architecture et réactivité de l'ARN, UPR 9002 CNRS, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg, France. e.ennifar@ibmc.u-strasbg.fr
Paillart
Jean-Christophe
JC
Bernacchi
Serena
S
Walter
Philippe
P
Pale
Patrick
P
Decout
Jean-Luc
JL
Marquet
Roland
R
Dumas
Philippe
P
D000617:Aminoglycosides / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D019281:Dimerization; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D000617:Aminoglycosides; D012367:RNA, Viral