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

Type of activity
Competitive project
Acronym
ATrich-DNA
Funding entity
ALBA - Consorcio para la Construcción, Equipamento y Explotación del Laboratorio de Luz de Sincrotrón
Funding entity code
2018093030
Start date
2019-01-21
End date
2019-11-29
Abstract
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 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. 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. 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 with a drug that interact with all AT sequence and cause disintegration of Trypanosome brucei kinetoplast. We observed curative activity in 100% of a mouse model of Human African Trypanosomiasis.

Participants