Structural Biology
Group Head: Dr Mika Jormakka
The Structural Biology Group is currently focusing on structural studies of membrane proteins involved in cellular respiration, cell signalling and transport. Of particular interest is transporters involved in cellular drug extrusion - these are proteins 'pumping' drugs out from the cell - and therefore reduce the efficiency of, for example, cancer chemotherapy and antibiotics. We hope to increase our understanding of these processes by obtaining structural information of these multi-drug transporters, to pave the way for therapeutic design.
In addition, we hope to provide comprehensive structural information of the quinone reduction/oxidation cycle in cellular respiration for continued development of anti-microbial inhibitors and pesticides.
Research focus
The recently established structural biology program at Centenary Institute is focused on elucidating 3D structures of membrane proteins involved in fundamental cellular processes by x-ray crystallography. Membrane proteins constitute roughly a third of the genes in genomes and perform a plethora of essential cellular functions. Their importance is reflected in that they represent 50-70 per cent of all pharmacological therapeutic targets. Structural biology, and the use of X-ray crystallography, provides a precise and detailed model of how a protein is folded in space. This enables us to understand the mechanism by which a protein function, and also provide a route to structure based drug discovery. Of particular interest to this laboratory are structural studies of membrane proteins relevant to human disease and disorders, such as drug extrusion and respiratory disorders.
Membrane transporters are involved in cellular influx and efflux of nutrients, ions and drugs. As such, they fill an essential niche in cellular homeostasis and are, in many cases, implicated in bacterial virulence, as well as drug extrusion, with important implications for cancer and anti-microbial drug resistance. Our studies are focused on multi-drug transporters belonging to the novel ‘multi-drug and toxin extrusion’ (MATE) family.
Signal transduction at the cellular level refers to the movement of signals from outside the cell to inside. Many disease processes such as diabetes, heart disease, autoimmunity and cancer arise from defects in signal transduction pathways, further highlighting the critical importance of signal transduction to biology as well as medicine. Central in human signal transduction is G-protein coupled receptors (GPCR). These are receptors localised in the membrane, sensing external stimuli, which is then translated to a cellular response. Of particular interest in our group are receptors involved in regulation of glucose levels in our blood system and their potential as targets for therapeutic drug design.
Respiratory enzymes have their main function in generating a proton motive force (PMF) across the membrane. The PMF has a pH and an electrical component, which is utilised by other membrane processes, such as ATP synthase, membrane transport, and signalling. Aerobic respiratory chain is composed of four large multi-subunit membrane proteins, Complex I-IV, of which II-IV have been structurally determined. In addition to aerobic respiration, many bacteria are able to induce ‘alternative’ respiratory pathways using terminal electron acceptors other than molecular oxygen, such as nitrate, sulphur, and iron. This enables human pathogens, including enterohaemorrhagic E. coli and Pseudomonas aeruginosa, to respire in anoxic environments, such as gut and mucus. We are interested in structural studies of both pathways, where we seek to obtain detailed information of the redox reactions taking place, understanding proton translocation processes, and to acquire detailed structural information of quinone redox reactions, which are ubiquitous for life.
