Laboratory of Molecular Biophysics
Laboratory Journal 2000
Dr. S. M. Lea

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Susan M. Lea

Towards a structural understanding of pathogenesis.

Knowledge of the way in which an invading pathogen interacts with its host at a molecular level is an essential aid to understanding the nature and extent of disease caused. My group aims to use a variety of techniques to probe the interactions that characterise different disease processes. Central to this approach is the use of X-ray crystallography to determine the structures of individual host or pathogen components, with a view in the longer term to examining the atomic structure of important host- pathogen complexes. The major targets are protein based but we are also involved in projects where folded RNAs provide the structural target.To aid understanding of biochemical and structural data we use a variety of other biophysical techniques (including surface plasmon resonance) to further characterise the biological systems under study.

The Complement System.

The complement system is a highly evolved system of proteins which together constitute a major element of host defences, functioning in both innate and adaptive immunity. Activation of complement by bacterial or other pathogens proceeds through enzymatic amplification steps (which are tightly regulated by specific proteins) to generate protein fragments and complexes which mediate acute inflammatory reactions, clearance of foreign cells and killing of invading pathogenic organisms. Conditions which result in misguided, excessive or uncontrolled activation of complement lead to human disease. Several projects aim to increase the understanding of the regulation of the complement system at the molecular level

Host-pathogen interactions

The moment at which a pathogen interacts specifically with a human cell provides a natural target for drug interference, as the interaction with a host protein requires maintenance of a constant surface on the pathogen which may then be targeted by drug designers. We are studying pathogen-receptor interactions which involve interactions with cell surface molecules, which then facilitate entry of the pathogen into, and hence infection of, a cell and also interactions between pathogen derived molecules and intra- cellular host proteins.

Bacterial Chemosensing Pathways: structural studies on pathway components and regulatory protein-protein interactions.

Changes in the motile behavior of bacteria, in response to chemosensory signals, are mediated by a series of intracellular protein/protein interactions. The chemotatic response is prevaricated by membrane bound methyl-accepting chemotaxis receptor proteins (MCPs) and/or intracellular transducer-like proteins (TLPs). MCPs and TLPs induce transduction of a signal to the flagella motor via a series of intracellular chemotatic proteins (Che proteins).

The interactions of these proteins have mainly been characterized through genetic study. However, surface plasmon resonance (SPR) is technique that can be used study the protein/protein interaction. In our present study SPR has been used to investigate several recombinant R. sphaeroides proteins involved in the chemotatic pathway in order to understand the dynamics and kinetics of this system.