DNA bending and unwinding associated with actinomycin D antibiotics bound to partially overlapping sites on DNA.

摘要: Actinomycin D (ActD) is a potent anti-tumor antibiotic, that preferentially targets (G-C).(G-C) steps on duplex DNA. We have reported the solution structure of ActD-d(A-A-A-G-C-T-T-T) complex (one drug per duplex) based combined application NMR and molecular dynamics calculations. This study established ActD binds to DNA through intercalation phenoxazone chromophore between with benzenoid quinonoid-linked cyclic pentapeptide lactone rings spanning two base-pairs in opposite directions minor groove helix. research now extended binding molecules adjacent complexation sites within (G-C-G-C).(G-C-G-C) segment self-complementary d(A1-A2-G3-C4-G5-C6-T7-T8) duplex. The occupation central (C4-G5).(C4-G5) by inwardly pointing from bound should result potential steric clash center data its analysis ActD-d(A-A-G-C-G-C-T-T) (two drugs establish intercalate into symmetry-related (G3-C4).(G5-C6) their attached quinonoid positioned directed towards ends helix, respectively. was solved using restraints guide distance geometry-simulated annealing restrained calculations including intensity-based refinements. helix exhibits pronounced kink fully unwound at step which results an opening widening generate additional space for accommodation complex. outwardly retain similar conformations largest difference observed L-MeVal residues present defines how structural changes primarily associated directional bending major away opens up widens accommodate intercalated partially overlapping