High-resolution crystal structure of the intramolecular d(TpA) thymine-adenine photoadduct and its mechanistic implications.

A high-resolution crystal structure is reported for d(TpA)*, the intramolecular thymine-adenine photoadduct that is produced by direct ultraviolet excitation of the dinucleoside monophosphate d(TpA). It confirms the presence of a central 1,3-diazacyclooctatriene ring linking the remnants of the T and A bases, as previously deduced from heteronuclear NMR measurements by Zhao et al. (The structure of d(TpA)*, the major photoproduct of thymidylyl-(3'-5')-deoxyadenosine.

Out-of-shape DNA minor groove binders: induced fit interactions of heterocyclic dications with the DNA minor groove.

DB921 and DB911 are benzimidazole-biphenyl isomers with terminal charged amidines. DB911 has a central meta-substituted phenyl that gives it a shape similar to those of known minor groove binding compounds. DB921 has a central para-substituted phenyl with a linear conformation that lacks the appropriate radius of curvature to match the groove shape.

Targeting the DNA minor groove with fused ring dicationic compounds: comparison of in silico screening and a high-resolution crystal structure.

The crystal structure of the DNA minor groove biphenyl benzimidazole diamidine ligand DB819 has been determined, bound to the DNA sequence d(CGCGAATTCGCG)(2), at a resolution of 1.36 Angstrom. Conditions for reliable in silico docking that reproduce the observed position of the ligand in the minor groove have been determined.

Thiophene-based diamidine forms a "super" at binding minor groove agent.

The DNA minor groove is the interaction site for many enzymes and transcription control proteins and as a result, development of compounds that target the minor groove is an active research area. In an effort to develop biologically active minor groove agents, we are preparing and exploring the DNA interactions of a systematic set of diamidine derivatives with a powerful array of methods including DNase I footprinting, biosensor-SPR methods, and X-ray crystallography. Surprisingly, conversion of the parent phenyl-furan-phenyl diamidine to a phenyl-thiophene-benzimidazole derivative yields a compound with over 10-fold-increased affinity for the minor groove at AT sequences.

Strong binding in the DNA minor groove by an aromatic diamidine with a shape that does not match the curvature of the groove.

A combination of biophysical techniques has been used to characterize the interaction of an antitrypanosomal agent, CGP 40215A, with DNA. The results from a broad array of methods (DNase I footprinting, surface plasmon resonance, X-ray crystallography, and molecular dynamics) indicate that this compound binds to the minor groove of AT DNA sequences. Despite its unusual linear shape that is not complementary to that of the DNA groove, a high binding affinity was observed in comparison with other similar but more curved diamidine compounds.

Crystal structure of parallel quadruplexes from human telomeric DNA.

Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, are fundamental in protecting the cell from recombination and degradation. Disruption of telomere maintenance leads to eventual cell death, which can be exploited for therapeutic intervention in cancer. Telomeric DNA sequences can form four-stranded (quadruplex) structures, which may be involved in the structure of telomere ends.