HIV‐1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations |
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Authors: | Jean‐François Mouscadet Rohit Arora Joseph André Jean‐Christophe Lambry Olivier Delelis Isabelle Malet Anne‐Geneviève Marcelin Vincent Calvez Luba Tchertanov |
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Institution: | 1. LBPA, CNRS, Ecole Normale Supérieure de Cachan, 61 Avenue du Président Wilson, 94235 Cachan, France;2. Laboratoire d'Optique et Biosciences, Ecole Polytechnique, 91128 Palaiseau, France;3. Laboratoire de Virologie, INSERM U943, H?pital Pitié‐Salpêtrière, Université Pierre et Marie Curie, 75013 Paris, France |
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Abstract: | Virologic failure during treatment with raltegravir, the first effective drug targeting HIV integrase, is associated with two exclusive pathways involving either Q148H/R/K, G140S/A or N155H mutations. We carried out a detailed analysis of the molecular and structural effects of these mutations. We observed no topological change in the integrase core domain, with conservation of a newly identified Ω‐shaped hairpin containing the Q148 residue, in particular. In contrast, the mutations greatly altered the specificity of DNA recognition by integrase. The native residues displayed a clear preference for adenine, whereas the mutant residues strongly favored pyrimidines. Raltegravir may bind to N155 and/or Q148 residues as an adenine bioisoster. This may account for the selected mutations impairing raltegravir binding while allowing alternative DNA recognition by integrase. This study opens up new opportunities for the design of integrase inhibitors active against raltegravir‐resistant viruses. Copyright © 2009 John Wiley & Sons, Ltd. |
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Keywords: | HIV‐1 IN resistance DNA recognition modeling crystallographic database analysis |
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