Devanathan Raghunathan - TAR-RNA recognition by a novel cyclic aminoglycoside analogue

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  Nucl. Acids Res.    (2006)   34   (12):3599-3608.



    The formation of the Tat-protein/TAR-RNA complex is a crucial   step in the regulation of human immunodeficiency virus (HIV)-gene   expression. To obtain full-length viral transcripts the Tat/TAR   complex has to recruit the positive transcription elongation   factor complex (P-EFTb), which interacts with TAR through its   cyclin T1 (CycT1) component. Mutational studies identified the   TAR hexanucleotide loop as a crucial region for contacting CycT1.   Interfering with the interaction between the Tat/CycT1 complex   and the TAR-RNA is an attractive strategy for the design of   anti-HIV drugs. Positively charged molecules, like   aminoglycosides or peptidomimetics, bind the TAR-RNA, disrupting   the Tat/TAR complex. Here, we investigate the complex between the   HIV-2 TAR-RNA and a neooligoaminodeoxysaccharide by NMR   spectroscopy. In contrast to other aminoglycosides, this novel   aminoglycoside analogue contacts simultaneously the bulge   residues required for Tat binding and the A35 residue of the   hexanucleotide loop. Upon complex formation, the loop region   undergoes profound conformational changes. The novel binding   mode, together with the easy accessibility of derivatives for the   neooligoaminodeoxysaccharide, could open the way to the design of   a new class of TAR-RNA binders, which simultaneously inhibit the   formation of both the Tat/TAR binary complex and the   Tat/TAR/CycT1 ternary complex by obstructing both the bulge and   loop regions of the RNA.

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