Book of Abstracts: Albany 2005
A New DNA Quadruplex That Inhibits HIV-1 Integrase
We present the solution structure of the 93del d(GGGGTGGGAGGAGGGT) aptamer, a potent nanomolar inhibitor of HIV-1 integrase (1). We establish that this 16-nucleotide DNA sequence adopts an unusually stable dimeric quadruplex architecture in K+ solution. The structure of each monomer subunit contains two G·G·G·G tetrads and one A·(G·G·G·G) pentad, where all G-stretches are parallel and linked by three single-nucleotide double-chain-reversal loops. Results of NMR and of integrase inhibition assays on loop-modified sequences allowed us to propose a new strategy towards the potential design of improved HIV-1 integrase inhibitors. Finally, we propose a model, based on molecular docking approaches, for positioning the 93del dimeric DNA quadruplex within a basic channel/canyon formed between subunits of a dimer of dimers of HIV-1 integrase (2).
Reference and Footnotes
1Structural Biology Program