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Structural studies of DNA sequences rich in adenine-thymine and their complexes with Minor groove binder drugs, peptides and HMG proteins

Type of activity
Competitive project
Funding entity
ALBA - Consorcio para la Construcción, Equipamento y Explotación del Laboratorio de Luz de Sincrotrón
Start date
End date
Abstract: Progress in genome sequencing has shown a large number of the control and repetitive sequences rich in AT bases. There is very little information on the structure of such sequences.
Therefore we are studying them by single crystal X-ray diffraction, with surprising results, some DNA fragments which only contain A•T base pairs form supercoiled structures with a large number
of oligonucleotides in the asymmetric unit. DNA supercoiled structures had never been previously studied by X-ray crystallography. Preliminary results was obtained at the ID14 line (ESRF). We expect to reach 2-3 Å resolution by using even smaller crystals, in particular crystalline cubes and rods of 10-30 m diameter. Furthermore one of the parameters of the unit cell (216-1000 Å) and mosaicity are very large, spots tend to overlap and a narrow beam is required. When c is very large we require an accurate orientation of the crystal, only possible in the Xaloc line of Alba Synchrotron. More recently we have found that some drugs may act as cross-linking agents for DNA. We plan to explore the interaction of related drugs with 100% AT sequence. We will study
minor groove binding drugs, which have been used as anti-protozoal agents in the fight against malaria, trypanosomiasis and leishmaniosis. We already have good results in this. Furthermore we
have started the study of the interaction of DNA with High Mobility Group proteins (HMG) and related peptides. The HMGA proteins are found in all cells and interact with AT rich regions of DNA. We have recently discovered that the box-A domain, part of HMGB1 protein, can underwind and dramatically kink (85º) an AT-rich DNA.