Binding of neomycin to the TAR element of HIV-1 RNA induces dissociation of Tat protein by an allosteric mechanism

Biochemistry
S WangH Y Mei

Abstract

Neomycin inhibits the binding of Tat-derived peptides to the trans-activating region (TAR) of HIV-1 RNA. Kinetic studies reveal that neomycin acts as a noncompetitive inhibitor that can bind to the Tat-TAR complex and increase the rate constant (koff) for dissociation of the peptide from the RNA. Neomycin effects a conformational change in the structure of TAR that can be detected by circular dichroism spectroscopy. The increase in ellipticity measured at 265 nm upon binding of the aminoglycoside is opposite to the decrease seen when Tat peptides bind to the RNA. Thus, the structural transition induced by neomycin is apparently incompatible with the binding of Tat and underlies the inhibitory action of the antibiotic. The binding site for neomycin on TAR was identified in ribonuclease protection experiments and is located in the stem immediately below the three-nucleotide bulge that serves as the primary identity element for Tat. Apparent protection of residues in the bulge by neomycin may represent additional contacts to the aminoglycoside, but more likely result from changes in the structure of this region when the ligand binds to the RNA. Binding assays using variants of TAR in which inosine residues were substituted for gua...Continue Reading

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