The Oxford Science Lecture Series

Professor Jenny Martin

University of Queensland, Australia

"The name’s Bond …… Disulphide Bond"

9th Dorothy Hodgkin Memorial Lecture

University Museum, Oxford, 6th March 2007

Professor Jenny Martin is an Australian Research Council Professorial Research Fellow in the Institute for Molecular Bioscience at the University of Queensland, Brisbane, Australia. She was awarded a D Phil (Oxon) in 1990 on the structure-based design of glycogen phosphorylase inhibitors as potential anti-diabetics, supervised by Professors Louise Johnson (who in turn was supervised by Dorothy Hodgkin) and Peter Goodford. This was followed by a post-doctoral stint at Rockefeller University in New York with Professor John Kuriyan (working on E coli DsbA, the first Dsb protein to be structurally characterized) and she then set up her own lab in Brisbane in 1993 where she investigates the structure, function and inhibition of proteins important in disease. Her achievements have been recognised recently by the award of the 2005 Roche Medal of the Australian Society for Biochemistry and Molecular Biology and the 2005 Queensland Government Smart Women Smart State Award (Research Scientist category). Jenny is the Immediate Past President of the Society for Crystallography in Australia and New Zealand, a member of the National Scientific Advisory Board of the Australian Synchrotron (due to open Apr 2007 in Melbourne) and a member of the National Science and Technology Centre in Canberra.

In keeping with the title, the Jenny Martin began her lecture by illustrating the transformation of a dithiol into a disulphide bond accompanied by the James Bond theme tune! She gave a brief overview of the history of X-ray crystallography and of Dorothy Hodgkin’s many achievements in that field. She explained how the technique is applied to establish the crystal structure of protein molecules and how that information can be used to deduce the function of the protein. She explained this “structure-function relationship” by referring to the structure and function of dogs. Although all dogs are similar in that they have 4 legs, 2 ears, a tail and fur, by looking at their structure one can deduce much about their function. For example an Alsatian is a strong muscular dog and is used for security and guard-dog functions, whilst a Bloodhound has a large nose ideal for tracking. Once one has established the structure and function of a protein, one can investigate how to affect that function using drug design.

Disulphide bonds are covalent bonds between strands of a protein molecule which act as a brace for the protein structure and help to stabilise it. This is particularly important in proteins which are secreted outside the cell into an environment where they need to be robust. The virulence of bacteria is reliant on secreted proteins stabilised by disulphide bonds. The Dsb family of proteins, studied by Jenny Martin, are involved in the formation of these stabilising disulphide bonds. She explained how, by inhibiting the activity of Dsb proteins in bacteria, the folding and stability of the molecules they secreted are impaired and the bacteria cease to function effectively. In the final part of her lecture, Jenny Martin described how, using structure-based drug design, she is working towards inhibiting the function of bacteria like Wolbachia which infects insects, worms and spiders and is involved in diseases such as river blindness. Wolbachia lives in mature eggs but not mature sperm and is transmitted from mother to daughter. Infection causes spontaneous development of eggs (without the requirement for sperm) and/or killing or feminisation of males! As Wolbachia secretes proteins stabilised by disulphide bonds, Jenny Martin has isolated the Dsb protein from Wolbachia and solved the crystal structure so that she can develop molecules which will be used to break this cycle of disease.

As is customary for the Dorothy Hodgkin Lecture, the event concluded with wine and nibbles downstairs in the University Museum, amongst the dinosaurs and dodos, enabling one to question the speaker further and to soak up the atmosphere of the building where Dorothy Hodgkin pursued much of her research.

Dr Carolyn Carr, Cardiac Metabolism Research Group, University of Oxford.