Director:   
Professor Stephen Neidle DSc, PhD, ARCS, FRSC

About the Centre

The recognition of nucleic acid sequence and structure is fundamental to many cellular processes. Our goal is to understand the molecular basis of these processes by studying nucleic acid recognition by small molecules, nucleic acids themselves, and by proteins. Our approach is to analyse the molecular structures of nucleic acids and their complexes by means of X-ray crystallography and molecular modelling/simulation methods. We are also applying this knowledge to the rational design of novel small-molecule inhibitors for potential use as selective anticancer agents.

Research programme

Studies of telomeric DNA and design of G-quadruplex inhibitors

The ends of chromosomes consist of specialised guanine-rich sequences. In homo sapiens the extreme ends are single stranded for up to 200 bases in length. These sequences can fold up in a variety of ways to form four-stranded structures, termed quadruplexes. We are using X-ray crystallography to define their three-dimensional structures, and we have recently found a novel arrangement for quadruplexes formed from human telomeric DNA sequences. [See Parkinson, G.N., Lee, M.P.H. & Neidle, S. Crystal structures of parallel quadruplexes from human telomeric DNA. Nature, 2002, 417, 876-880 for further details]

Crystallography and NMR

We have determined crystal structures of a number of telomeric DNA quadruplexes and their ligand complexes - see the publications pages for further details.

We have excellent facilities, with an in-house RIGAKU image plate system with low-temperature facilities, and a robotic system. The crystallography laboratory also has facilities for in-house oligonucleotide synthesis and purifications.

Our unprecedented and unexpected parallel structure for the human intramolecular telomeric quadruplex has generated much interest (over 250 citations to date), as well as considerable controversy!

More recently, in collaboration with Dinshaw Patel and his colleagues at the Memorial Sloan-Kettering Cancer Centre, the NMR structure of a quadruplex formed from a sequence in the c-kit gene has been determined. This remarkable structure has a very novel quadruplex topology.

Chemical Biology

Much of what we do is at the interface between chemistry and biology. Typically molecules designed and synthesised in our chemistry laboratories are also evaluated in cancer cell lines, often by the same person. Our PhD program actively encourage students to experience at first hand the synthesis of some novel molecules and then a study of their biological mechanism of action.

Synthetic chemistry is currently focussed on the synthesis of novel and selective a quadruplex-binding molecules. Biological studies range from traditional evaluations of short-term growth inhibition with a panel of cancer and normal cell lines, to examination of gene expression using RT-PCR and gene arrays.

Modelling, simulations and bioinformatics

The Group has a long tradition of using molecular modelling to study nucleic acid structure in association with experimental studies. Current activities include molecular dynamics simulation of multi-quadruplex arrangements, free-energy calculations of binding energies, and in silico library screening. We have pioneered bioinformatic studies on quadruplex occurrences in the human and other genomes, and have developed dedicated software to undertake complex database searches. The Group is well-equipped for computational studies, with a network of workstations for visualisation and number-crunching, and a dedicated cluster for computer-intensive applications.

Funding

Our work is supported by Cancer Research UK , The Association for International Cancer Research , The European Union and BBSRC.  

Selected Publications

[Extended list of publications]