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Structure and function of DNA topoisomerases and associated proteins: their role in biological processes, and their exploitation in chemotherapeutics

Reference	BBS/E/J/00000201
Principal Investigator / Supervisor	Professor Anthony Maxwell
Co-Investigators / Co-Supervisors
Institution	John Innes Centre
Department	John Innes Centre Department
Funding type	Research
Value (£)	2,227,611
Status	Completed
Type	Institute Project
Start date	08/01/2000
End date	31/03/2017
Duration	206 months

Abstract

DNA topoisomerases are enzymes that control the topological state of DNA in cells. They are essential enzymes in both prokaryotes and eukaryotes and are important drug targets. We are studying the structure of these enzymes, their mechanisms of action and their interaction with antibiotics and other potential therapeutic agents. The overall objective is to obtain a full understanding of the structures and mechanisms of topoisomerases and establish their roles in key biological process, and to harness this knowledge for the development of antibacterial agents and herbicides. Specific questions that we aim to address include: investigating how type II topoisomerases catalyse reactions ‘beyond equilibrium’, and determining what implications this has for other energy-coupling systems; determining the role of gyrase in plant organellar replication, and the role of topo VI in plants, and establishing the functions of the accessory proteins Rhl1 and Bin4 in the topo VI complex; establishing how quinolones, simocyclinones and other antibiotics and toxins bind gyrase and topoisomerase IV, and to exploit this information to design better drugs; developing new lead molecules based on natural products, and determine the basis of the antibiotic-resistance mechanism(s) in the producing organisms. These questions will be addressed via number of approaches drawing on the foundations of previous work and utilising tractable microbial and plant enzymes/systems. Enzymes from the following organisms will be investigated: Escherichia coli, Staphylococcus aureus, Mycobacterium tuberculosis and Arabidopsis thaliana. Approaches to be taken will include biophysical methods: X-ray crystallography, NMR, mass spectrometry, surface plasmon resonance, isothermal titration calorimetry; biochemical approaches, including enzymological methods; and a range of plant and microbial molecular biology approaches.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Pharmaceuticals, Plant Science, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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