Nucleic Acids Research, Vol 25, Issue 22 4487-4492, Copyright © 1997 by Oxford University Press
L Dassonneville, F Hamy, P Colson, C Houssier and C Bailly
The transactivation response region (TAR) RNA is an essential component in
transcriptional regulation of the human immunodeficiency virus type- 1
(HIV-1) genome. We have examined the interaction between TAR RNA and the
bisbenzimidazole derivative Hoechst 33258. Previous studies have shown that
this drug, which is well known as an AT-selective DNA minor groove binder,
can also interact with GC-rich sequences in DNA as well as with RNA,
possibly by intercalation. Absorption spectroscopy, circular dichroism and
electric linear dichroism, as well as RNase A footprinting, were employed
to compare binding of Hoechst 33258 to wild- type RNA and its analogue
lacking the pyrimidine bulge. The uridine bulge, which is an important
contributor to the structural stability of TAR, plays an essential role in
drug binding. Deletion of the bulge destabilizes both free and drug-bound
forms of TAR and markedly affects the orientation of the drug chromophore
complexed with the RNA. According to the linear dichroism data, the
bisbenzimidazole is oriented more or less perpendicular to the RNA helix
axis. The data are compatible with a model in which the bisbenzimidazole
chromophore is inserted into the existing cavity created by the pyrimidine
bulge. The footprinting experiments, showing that the drug binds to a
unique site opposite the unpaired uridine residues, also support this
model. The binding of Hoechst 33258 to the sequence 5'-GCUCU, which
delimits the cavity, reflects the greater accessibility of that region
compared with other sites in the RNA molecule. The identification of a
binding site for small molecules in TAR offers promising perspectives for
developing drugs that would block the access of TAR RNA to proteins and
therefore for the design of anti-HIV agents.
ARTICLES
Binding of Hoechst 33258 to the TAR RNA of HIV-1. Recognition of a pyrimidine bulge-dependent structure
Laboratoire de Pharmacologie Moleculaire Antitumorale du Centre Oscar Lambret et INSERM Unite 124, Place de Verdun, 59045 Lille, France.
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