Interaction of the antitumour antibiotic luzopeptin with the hexanucleotide duplex d(5′-GCATGC)2. One-dimensional and two-dimensional n.m.r. studies

摘要: 1H- and 31P-n.m.r. spectroscopy were used to characterize the solution structure of 1:1 complex formed between antitumour antibiotic luzopeptin self-complementary hexanucleotide d(59-GCATGC)2. Eighteen nuclear Overhauser effects nucleotide protons, together with ring-current-induced perturbations base-pair quinoline 1H resonances, define position orientation bound drug molecule. Luzopeptin binds in minor groove DNA full retention dyad symmetry, its chromophores intercalating at 59-CpA 59-TpG steps depsipeptide ring spanning central two A.T base-pairs. The stack principally on adenine base their carbocyclic rings pointing towards deoxyribose cytosine. There is no evidence for Hoogsteen base-pairing complex, all glycosidic bond angles sugar puckers being typical B-DNA as found free hexanucleotide. ‘breathing’ motions internal G.C base-pairs are substantially slowed compared DNA, observation that phosphate resonances shifted downfield by least 0.5 p.p.m. spectrum suggests pronounced local helix unwinding intercalation sites. data consistent a model which bisintercalates essentially conformation crystal [Arnold & Clardy (1981) J. Am. Chem. Soc. 103, 1243-1244]. We postulate only one conformational change within peptide ring, involves rotation pyridazine-glycine amide group linkage 90 degrees surface. This manoeuvre breaks glycine-to-glycine transannular hydrogen bonds enables glycine NH groups thymine O-2 atoms sandwiched It also shortens major axis so interchromophore distance more suitable further implies carboxy hydroxy L-beta-hydroxyvaline residue appropriately positioned hydrogen-bonding 2-amino guanine atom cytosine adjacent base-pair.