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J. Biol. Chem., Vol. 278, Issue 22, 19966-19973, May 30, 2003

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Strategy to Discriminate between High and Low Affinity Bindings of Human Immunodeficiency Virus, Type 1 Integrase to Viral DNA^*

Loussinée Zargarian , Mohamed Salah Benleumi , Jean-Guillaume Renisio , Hayate Merad , Richard G. Maroun  , Frédéric Wieber , Olivier Mauffret , Horea Porumb , Frédéric Troalen ¶ and Serge Fermandjian  ||

From the Département de Biologie et Pharmacologie Structurales, UMR 8113 CNRS, Institut Gustave Roussy, Villejuif 94805 and Ecole Normale Supérieure de Cachan, Cachan 94235, Département des Sciences de la Vie et de la Terre, Faculté des Sciences, Université Saint Joseph, CST-Mar Roukos, B.P. 1514, Beyrouth 1107 2050, Liban, and ^¶Laboratoire de Microchimie et d'Immunologie Moléculaire, Département de Biologie Clinique, Institut Gustave Roussy, Villejuif 94805, France

The last decade has contributed to our understanding of the three-dimensional structure of the human immunodeficiency virus, type 1 (HIV-1) integrase (IN) and to the description of how the enzyme catalyzes the viral DNA integration into the host DNA. Recognition of the viral DNA termini by IN is sequence-specific, and that of the host DNA does not require particular sequence, although in physicochemical studies IN fails to discriminate between the two interactions. Here, such discrimination was allowed thanks to a model system using designed oligonucleotides and peptides as binding structures. Spectroscopic (circular dichroism, NMR, and fluorescence anisotropy) techniques and biochemical (enzymatic and filter binding) assays clearly indicated that the amphipathic helix 4, located at the catalytic domain surface, is responsible for the specific high affinity binding of the enzyme to viral DNA. Analogues of the 4 peptide having increased helicity and still bearing the biologically relevant lysines 156 and 159 on the DNA binding face, and oligonucleotides conserving an intact attachment site, are required to achieve high affinity complexes (K_d of 1.5 nM). Data corroborate previous in vivo results obtained with mutated viruses.

Received for publication, November 18, 2002 , and in revised form, February 3, 2003.

^* This work was supported by a grant from SIDACTION. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Département de Biologie et Pharmacologie Structurales (CNRS UMR 8113), PR2, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel.: 33-0-1-42-11-49-85; Fax: 33-0-1-42-11-52-76; E-mail: sfermand{at}igr.fr.

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