Book of Abstracts: Albany 2005

category image Volume 22
No. 6
June 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
  1. Phan A. T., Kuryavyi V., Ma J. B., Faure, A., Andréola M. L., and Patel D.J. Proc. Natl. Acad. Sci. USA 102, 634-639 (2005).
  2. Wang, J. Y., Ling, H., Yang, W., and Craigie, R. EMBO J. 20, 7333-7343 (2001).

A.T. Phan1,*
V. Kuryavyi1
J.B. Ma1
A. Faure2
M.L. Andréola2
D.J. Patel1

1Structural Biology Program
Memorial Sloan-Kettering Cancer Center
New York, USA
Université Victor Segalen Bordeaux 2
Bordeaux, France

Phone: 1-212-639-2772
Fax: 1-212-717-3066
Email: phantuan@MSKCC.ORG