title: HIV-1 IN alternative molecular recognition of DNA induced by raltegravir resistance mutations.
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 Omega-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.
authors.affiliation: LBPA, CNRS, Ecole Normale Supérieure de Cachan, 61 Avenue du Président Wilson, 94235 Cachan, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: Rohit
authors.initials: R
authors.lastname: Arora
authors.forename: Joseph
authors.initials: J
authors.lastname: André
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Lambry
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Anne-Geneviève
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Luba
authors.initials: L
authors.lastname: Tchertanov
mesh_terms: D000225:Adenine / Q000737:chemistry; D020134:Catalytic Domain; D002412:Cations; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods; D004247:DNA / Q000737:chemistry*; D024882:Drug Resistance, Viral; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000235:genetics*; D006860:Hydrogen Bonding; D009154:Mutation; D017433:Protein Structure, Secondary; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D000068898:Raltegravir Potassium
chemical_list: D002412:Cations; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D004247:DNA; D019427:HIV Integrase; D000225:Adenine