Solution structure of the luzopeptin-DNA complex

Journal Article · Tue Apr 23 00:00:00 EDT 1991 · Biochemistry; (United States)

DOI:https://doi.org/10.1021/bi00230a030· OSTI ID:5594965

Zhang, Xiaolu; Patel, D J ^[1]

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1. Columbia Univ., New York, NY (USA)

The luzopeptin-d(C-A-T-G) complex (1 drug/duplex) has been generated in aqueous solution and its structure characterized by a combined application of two-dimensional NMR experiments and molecular dynamics calculations. Once equivalent of luzopeptin binds to the self-complementary tetranucleotide duplex with the 2-fold symmetry of the antitumor agent and the DNA oligomer retained on complex formation. The authors have assigned the exchangeable and nonexchangeable proton resonances of luzopeptin and the d(C-A-T-G) duplex in the complex and identified the intermolecular proton-proton NOEs that define the alignment of the antitumor agent at its binding site in duplex DNA. The analysis was greatly aided by a large number of intermolecular NOEs involving exchangeable protons on both the luzopeptin and the DNA in the complex. The formation of cis peptide bonds for luzopeptin in the complex results in an increased separation of the long sides of the rectangular cyclic depsipeptide backbone and reorients in the glycine amide proton so that it can form an intermolecular hydrogen bond with the 2-carbonyl of T3 in the complex. This observation explains, in part, the requirement for Watson-Crick A{center dot}T pairs to be sandwiched between the quinolines at the bisintercalation site in the luzopeptin-DNA complex. The NMR studies on the luzopeptin-d(C-A-T-G) complex unequivocally establish that antitumor agents can undergo conformational transitions on complex formation with DNA, and it is the conformation of the drug in the complex that should serve as the starting point for drug design studies. The above structural details on the solution structure of the luzopeptin-DNA complex also explain the sequence selectivity of luzopeptin for bisintercalation at d(C-A){center dot}d(T-G) steps in the d(C-A-T-G) duplex in solution.

• OSTI ID: 5594965
• Journal Information: Biochemistry; (United States), Journal Name: Biochemistry; (United States) Vol. 30:16; ISSN 0006-2960; ISSN BICHA
• Country of Publication: United States
• Language: English

Related Subjects

550601* -- Medicine-- Unsealed Radionuclides in Diagnostics
62 RADIOLOGY AND NUCLEAR MEDICINE
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
AQUEOUS SOLUTIONS
BARYONS
CHEMICAL SHIFT
DISPERSIONS
DNA
DRUGS
ELEMENTARY PARTICLES
FERMIONS
HADRONS
HEAVY WATER
HYDROGEN COMPOUNDS
MAGNETIC RESONANCE
MIXTURES
MOLECULAR STRUCTURE
NUCLEAR MAGNETIC RESONANCE
NUCLEIC ACIDS
NUCLEONS
OLIGONUCLEOTIDES
ORGANIC COMPOUNDS
OVERHAUSER EFFECT
OXYGEN COMPOUNDS
PROTONS
RESONANCE
SOLUTIONS
WATER