Polymorphism of bulged-out residues in HIV-1 RNA DIS kissing complex and structure comparison with solution studies.
All retroviruses encapsidate their genome as a dimer of homologous single-stranded RNAs. The dimerization initiation site (DIS) of human immunodeficiency virus type 1 (HIV-1) is located in the 5'-untranslated region of the viral genome and consists of a hairpin with a 6 nt self-complementary loop sequence. Genomic RNA dimerization, a crucial step for virion infectivity, is promoted by the formation of a loop-loop complex (or kissing complex) between two DIS hairpins. Crystal structures for the subtypes A, B and F of the HIV-1 DIS kissing complex have now been solved at 2.3 A, 1.9 A and 1.6 A, respectively. They revealed a polymorphism of bulged-out residues showing clearly that their conformation is not a mere consequence of crystal packing. They also provide more insights into ion binding, hydration, and RNA conformation and flexibility. In particular, we observed the binding of spermine to the loop-loop helix, which displaced a magnesium cation important for subtype A DIS dimerization. The excellent agreement between X-ray structures and the results of chemical probing and interference data on larger viral RNA fragments shows that the crystal structures are relevant for the DIS kissing complex present in solution and in viral particles. Accordingly, these structures will be helpful for designing new drugs derived from aminoglycoside antibiotics and targeted against the RNA dimerization step of the viral life-cycle.
Ennifar
Eric
E
UPR 9002 CNRS conventionnée à L'Université Louis Pasteur, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg, France. e.ennifar@ibmc.u-strasbg.fr
Dumas
Philippe
P
D020121:5' Untranslated Regions / Q000737:chemistry; D001665:Binding Sites / Q000235:genetics; D002413:Cations, Divalent; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D015497:HIV-1 / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D009690:Nucleic Acid Conformation; D011110:Polymorphism, Genetic; D011687:Purines / Q000737:chemistry; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics*; D012996:Solutions; D013096:Spermine / Q000737:chemistry; D014867:Water / Q000737:chemistry
D020121:5' Untranslated Regions; D002413:Cations, Divalent; D011687:Purines; D012367:RNA, Viral; D012996:Solutions; D014867:Water; D013096:Spermine