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J. Biol. Chem., Vol. 278, Issue 4, 2723-2730, January 24, 2003
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From the UPR9002-Institut de Biologie Moléculaire et
Cellulaire du CNRS, 15, rue René Descartes, F-67084
Strasbourg cedex, France
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.
HIV-1 RNA Dimerization Initiation Site Is
Structurally Similar to the Ribosomal A Site and Binds Aminoglycoside
Antibiotics*,
,
*
This work was supported by the "Agence Nationale de
Recherche sur le SIDA" (ANRS).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains supplementary data showing
audioradiographs of dimethyl sulfate (DMS) footprinting experiments in
the presence of increasing concentrations of neomycin with 1-615 RNA
fragments. Left, subtype A; middle, subtype A;
and right, mutant A278G. The probing reactions were carried
out for 0 (unmodified control), 5, and 10 min in 37 °C in the
absence (left panel) or in the presence of 10, 50, and 100 µM of neomycin. The position of the nucleotide whose
reactivity is changed (protection) upon the addition of antibiotic is
indicated (position N1-A280 for subtype A RNA only). The
lanes labeled U, A, C, and
G correspond to dideoxy sequencing reactions.
A fellow of ANRS.
§
To whom correspondence should be addressed. Tel.:
33-388417052; Fax: 33-388602218; E-mail:
p.walter@ibmc.u-strasbg.fr.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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