Membrane protein structure and interactions
Membrane proteins represent a significant challenge in structural biology. While it is estimated that a third of the human genome encodes for membrane proteins, the structures of relatively few membrane proteins are currently known. It will be some time before membrane protein structure determination becomes routine, yet over 40% of the drugs on the market today rely on the activity of membrane proteins for their efficacy. This project seeks to develop and apply novel techniques and approaches to study the structure and interactions of membrane proteins. A range of techniques for studying membrane interactions, including biosensor, fluorescence and NMR technologies, are being used for the study of membrane proteins.
Biologically active peptides: the relationship between structure and activity
We have identified peptides from the skin glands of frogs and toads which are amongst the most powerful biologically active compounds in the animal kingdom. The aims of this project are to investigate the relationship between the structure and biologically activity of chosen groups of peptides including pheromones, anticancer and antibiotic peptides, and peptides which inhibit neuronal nitric oxide synthase. Possible applications would be of major benefit to society, e.g. if the sex pheromone of the cane toad could be used to reduce its population, or if an anti-cancer active peptide of clinical applicability could be produced. Solid-state NMR is being used to determine the insertion and structure of these peptides in model membranes, since these peptides act by lysing bacterial or animal membranes. Frogs thwart superbugs
Membrane interactions and neurotoxicity of Amyloid Abeta peptides from Alzheimer’s disease
A consequence of the increase in human life span is that age-related neurodegenerative diseases such as Alzheimer’s disease (AD) are more prevalent. Currently there are limited therapeutic treatments and no cure for AD. AD is characterized by the abnormal accumulation of amyloid beta peptide (Abeta) into insoluble aggregates called plaques but increasing evidence indicates that the soluble form of Abeta is the toxic species. Abeta-induced toxicity may be mediated by binding to phospholipids in cell membranes. If so, drugs may be developed to prevent Abeta binding and lead to neuronal survival and prevention of memory loss in AD patients. We seek to determine if there is a link between Abeta neurotoxicity and membrane binding; and if metal ions modulate the membrane interaction. Co-localization of Abeta in model and cell membranes is being studied by solid-state NMR and fluorescence techniques.
Membrane structure and lipid interactions of pore-forming toxins by NMR.
The structure of the pore-forming proteins, equinatoxin II and listeriolysin O, is being studied in model cell membranes using solid-state NMR spectroscopy. The relationship of molecular structure to bioactivity and the nature of the pore-forming mechanism of the toxin will be determined (Toxins by NMR). The results will aid in understanding how toxins lyse cells and could lead to the design of improved antibiotic peptides. Currently the structure of membrane proteins are difficult to determine and the newly developed techniques used for the structural determination of these membrane-associated proteins will be suitable for studying other membrane proteins and receptors of pharmaceutical importance. Listen to Up Close interview Pore me another: Understanding how toxins target & overcome membranes.