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History of the HeliX Group The original
aim of this group was to determine the mode of binding to DNA
of the DACA family of compounds. These compounds were developed by Professor Bill Denny and coworkers
in Auckland, New Zealand, under the auspices of the New Zealand cancer Society.
The original Irish grant (to Christine Cardin, of Trinity College Dublin,
and Laurence Wakelin, of University College Dublin) employed Deborah Wilcock
and Adrienne Adams (then Mrs Wakelin) to carry out crystallisation
experiments. Adrienne Adams, Harry Powell and Alan Todd
were responsible for the initial MAD experiments in Trieste which led to
the solution of the structure of the 9-amino-DACA
derivative bound to d(CGTACG)2 DNA. (see J. Med. Chem. 1999, 42,536-540).
The atomic resolution structure of this complex, which has recently been accepted for publication,
shows that the drug is able to adopt
multiple conformations when bound to DNA.
Since then the Helix Group has developed research into the DNA Holliday junction and quadruplex DNA. Dr. Jim Thorpe solved several structures showing how different metal ions affect the stacked-X conformation of the Holliday junction. He also initiated similar work on the quadruplex forming molecule d(GCATGCT)2, which has been continued by Yu Gan. We are currently investigating drug binding to both quadruplex and junction forming DNA. In a callaboration with Dr. Mark Searcey at the London School of Pharmacy, Anna Brogden has synthesised several bisintercalating molecules based on the original DACA family of monointercalators. The structure of one of these bound to the Holliday junction has already been solved, and shows the drug displacing adenine bases at the junction crossover. More recently, the work of the Helix Group has expanded to include a range of topics in protein crystallography as well as DNA crystallography. Susana Teixeira refined the structure of a xylanase at high resolution, in collaboration with the group of Richard Pickersgill in Reading's Institute of Food Research (see Acta Cryst. D57, 2002, 385-392). She is now working in Grenoble with the Deuteration Initiative and is a Visiting Fellow in our group. We are currently initiating collaborations with her in macromolecular perdeuteration and single crystal neutron diffraction. In 2002 we began liaising with Syngenta as part of Reading's Crystallography Partnership. Jane Wibley of Syngenta is a Visiting Fellow within the group and we have a jointly supervised PhD student, Isabel Moraes. She has solved the structures of several lead compounds bound to ACPER. We are also collaborating with Prof. Adrian Williams in the School of Pharmacy at Reading on engineering the crystal forming habit of proteins to improve delivery of protein therapeutics. |
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