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Nucleic Acids Research Advance Access published online on October 6, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp824
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

Specificity of LTR DNA recognition by a peptide mimicking the HIV-1 integrase {alpha}4 helix

Zeina Hobaika1, Loussine Zargarian1, Yves Boulard2, Richard G. Maroun3, Olivier Mauffret1 and Serge Fermandjian1,*

1Laboratoire de Biotechnologies et Pharmacologie génétique Appliquée (LBPA), UMR 8113 CNRS, Ecole Normale Supérieure de Cachan, 61 Avenue du Président Wilson, 94235 Cachan Cedex, 2CEA SACLAY, (DSV/iBiTec-S/SBIGeM/LBI), Bat.144, P.C. 22, 91191 Gif-sur-Yvette Cedex, France and 3Département des Sciences de la Vie et de la Terre, Faculté des Sciences, Université Saint-Joseph, CST-Mar Roukos, Beirut, Lebanon

*To whom correspondence should be addressed. Tel: +33 1 47 40 77 42; Fax: +33 1 47 40 76 71; Email: serge.fermandjian{at}lbpa.ens-cachan.fr

Received March 31, 2009. Revised September 16, 2009. Accepted September 18, 2009.

HIV-1 integrase integrates retroviral DNA through 3'-processing and strand transfer reactions in the presence of a divalent cation (Mg2+ or Mn2+). The {alpha}4 helix exposed at the catalytic core surface is essential to the specific recognition of viral DNA. To define group determinants of recognition, we used a model composed of a peptide analogue of the {alpha}4 helix, oligonucleotides mimicking processed and unprocessed U5 LTR end and 5 mM Mg2+. Circular dichroism, fluorescence and NMR experiments confirmed the implication of the {alpha}4 helix polar/charged face in specific and non-specific bindings to LTR ends. The specific binding requires unprocessed LTR ends—i.e. an unaltered 3'-processing site CA{downarrow}GT3'—and is reinforced by Mg2+ (Kd decreases from 2 to 0.8 nM). The latter likely interacts with the ApG and GpT3' steps of the 3'-processing site. With deletion of GT3', only persists non-specific binding (Kd of 100 µM). Proton chemical shift deviations showed that specific binding need conserved amino acids in the {alpha}4 helix and conserved nucleotide bases and backbone groups at LTR ends. We suggest a conserved recognition mechanism based on both direct and indirect readout and which is subject to evolutionary pressure.


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