title: An interlocked dimeric parallel-stranded DNA quadruplex: a potent inhibitor of HIV-1 integrase.
abstract: We report on the NMR-based solution structure of the 93del d(GGGGTGGGAGGAGGGT) aptamer, a potent nanomolar inhibitor of HIV-1 integrase. This guanine-rich DNA sequence adopts an unusually stable dimeric quadruplex architecture in K+ solution. Within each 16-nt monomer subunit, which contains one A.(G.G.G.G) pentad sandwiched between two G.G.G.G tetrads, all G-stretches are parallel, and all guanines are anti with the exception of G1, which is syn. Dimer formation is achieved through mutual pairing of G1 of one monomer, with G2, G6, and G13 of the other monomer, to complete G.G.G.G tetrad formation. There are three single-nucleotide double-chain-reversal loops within each monomer fold, such that the first (T5) and third (A12) loops bridge three G-tetrad layers, whereas the second (A9) loop bridges two G-tetrad layers and participates in A.(G.G.G.G) pentad formation. Results of NMR and of integrase inhibition assays on loop-modified sequences allowed us to propose a strategy toward 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.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Anh Tuân
authors.initials: AT
authors.lastname: Phan
authors.forename: Vitaly
authors.initials: V
authors.lastname: Kuryavyi
authors.forename: Jin-Biao
authors.initials: JB
authors.lastname: Ma
authors.forename: Aurélie
authors.initials: A
authors.lastname: Faure
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Andréola
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D015195:Drug Design; D054856:G-Quadruplexes; D019427:HIV Integrase / Q000737:chemistry*; D006801:Humans; D019429:Integrase Inhibitors / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D011188:Potassium
chemical_list: D019380:Anti-HIV Agents; D019429:Integrase Inhibitors; D004247:DNA; D019427:HIV Integrase; D011188:Potassium