A comparison of the structure of echinomycin and triostin A complexed to a DNA fragment

Abstract

Two members of the quinoxaline antibiotic family, echinomycin and triostin A, form crystals complexed to a DNA fragment with the sequence d(CpGpTpApCpG). The crystal structure of both complexes was solved by X-ray diffraction to near-atomic resolution. The two structures are similar to each other with differences in some details due to the shorter cross bridge of echinomycin. Both molecules act as bis intercalators surrounding the d(CpG) sequence at either end of the double helix. Alanine forms sequence-specific hydrogen bonds to guanines in the minor groove. The two central AT base pairs are held together by Hoogsteen base pairing with adenine in the syn conformation in both complexes. An octahedrally hydrated magnesium ion is found in the crystal lattice that plays an important role in organizing the lattice as well as stabilizing the complex by hydrogen bonding both to base pairs of DNA and to the quinoxaline ring nitrogen atoms in the major groove side of the DNA double helix. A functional description of the various amino acids in quinoxaline antibiotics is given, together with possible modifications that might affect biological activity.

DNA recognition by quinoxaline antibiotics: use of base-modified DNA molecules to investigate determinants of sequence-specific binding of triostin A and TANDEM

“…Most binding studies have been performed with [N-MeCys$, NMeCys(]TANDEM rather than with TANDEM itself, but the two synthetic drugs appear equivalent in terms of binding strength and specificity. Several structures of triostin A, TAN-DEM and [N-MeCys$, N-MeCys(]TANDEM bound to short duplex oligonucleotides have been elucidated by crystallography and NMR [18][19][20][21][22][23][24][25]. In general, the bis-intercalated complexes are comparable.…”

Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322.

“…X-ray crystallography has served as the primary vehicle for elucidating the nonbonded interactions between the host nucleic acid and guest molecules (3) that include water (4), linked heterocycles [e.g., netropsin (5), echinomycin (6)], fused aromatics [e.g., triostin A (7), daunomycin (8)], and peptides [e.g., trp repressor (9), phage 434 Cro (10)]. NMR spectroscopy (11) and molecular modeling (12) have contributed additional understanding into these systems and others that have not yielded to the demands of the former technique.…”

Exploring the Biosynthesis of Natural Products and Their Inherent Suitability for the Rational Design of Desirable Compounds through Genetic Engineering

“…As judged by detailed X-ray, NMR structural, and other biophysical studies of these molecules, heteroaromatic planar chromophores, the invariant feature of quinomycin antibiotics, provide these compounds with the ability to bis-intercalate tightly into DNA. [52][53][54] In addition, a comparative study of echinomycin and SW-163D [55][56][57][58] found that the type of chromophore in the compounds influences their sequence selectivity. 59) However, the cyclic peptide backbone of these molecules, while providing a rigid framework that holds the chromophores in place for effective DNA intercalation, also plays an important role in determining the binding sequence specificity of these antibiotics, primarily by forming hydrogen bonds with the base moieties in the minor groove.…”

“…59) However, the cyclic peptide backbone of these molecules, while providing a rigid framework that holds the chromophores in place for effective DNA intercalation, also plays an important role in determining the binding sequence specificity of these antibiotics, primarily by forming hydrogen bonds with the base moieties in the minor groove. [52][53][54] Furthermore, modification of the cross-bridge provides further finetuning of the binding site selectivity of these quinomycin antibiotics. This was illustrated by DNA-binding studies on echinomyicn and its close relative, triostin A.…”