A research unit set up 18 months ago to investigate the structure of proteins has already made several significant discoveries and, with a synchrotron being built at Monash University's Clayton campus, its future looks all the brighter. PENNY FANNIN reports.
|Dr Jamie Rossjohn
Growing in the laboratories of Monash's Department of Biochemistry and Molecular Biology are protein crystals from many different organisms. Blue protein crystals from a coral found on the Great Barrier Reef sit in crystallisation trays alongside golden crystals of a human T-cell receptor.
Such crystals are the centrepiece of the university's Protein Crystallography Unit (PCU), established in the School of Biomedical Sciences at the Clayton campus in January 2002.
Dr Jamie Rossjohn, a Wellcome Trust senior research fellow, was recruited from St Vincent's Institute of Medical Research to head the PCU. In its 18 months of operation, the unit has worked out the structures of numerous important proteins, providing unique insights into their function. These include:
- the crystal structure of a key receptor in multiple sclerosis;
- discovering a group of proteins in bacteria called serpins that have exposed a new mechanism for preventing a range of human diseases;
- the crystal structure of a human T-cell receptor (receptors are a group of proteins that other proteins bind to) and the structure of this receptor in complex with a peptide from the Epstein Barr Virus. Also solved were the crystal structures of related receptors, called HLA B44, which are a significant barrier in human organ transplantation;
- finding that the protein that gives reef-building corals their blue colour could be useful as a biotechnological tool capable of highlighting structures and interactions within cells.
The protein is already being used as a fluorescent probe by Monash scientists to monitor proteins in cells.
Protein crystallography is a major technique for solving the 3D structure of proteins and uses X-rays to provide unparalleled information on the structure and function of proteins. It is also an important means of rational drug design, the design and development of therapeutics that can bind to a protein, thereby preventing or promoting its action.
"Proteins are the molecular machines of our body, and their malfunction is the basis of many diseases," Dr Rossjohn says. "Knowing the three-dimensional structure of a protein gives an understanding, at the atomic level, of how a protein functions, or in the diseased state, of how it malfunctions."
Despite the fundamental contribution that protein crystallography can make to understanding disease and developing therapeutics, the School of Biomedical Sciences did not have a unit that could undertake such research until recently. But the persistence of Professor Warwick Anderson, Mr Ian Macfarlane, Professor Christina Mitchell, Dr Rossjohn and Dr James Whisstock made it a reality.
Funding for the million-dollar unit came from the Ian Potter Foundation, the National Health and Medical Research Council, the Victorian Government and Monash.
The PCU has four laboratories - a main laboratory where proteins for study are purified, a crystallisation laboratory, an X-ray diffraction laboratory and a graphic laboratory where crystal structures are determined and built using common crystallographic software packages.
"To undertake a crystallography project, we need to obtain crystals of the protein," says Dr Rossjohn. "A protein in isolation is too small to study by X-ray crystallography, but a protein crystal contains numerous copies of the protein."
For a protein to be 'seen', it must be bombarded with X-ray light. Although the PCU has an X-ray diffraction laboratory, Dr Rossjohn and other crystallographers frequently visit overseas synchrotron facilities, where more intense X-rays are available.
|Dr James Whisstock
Earlier this year, Dr Whisstock, scientific director of the Victorian Bioinformatics Consortium (VBC), used X-ray crystallography and synchrotron radiation at the Advanced Photon Source in Chicago to solve the structure of a bacterial protein called a serpin.
Australia's synchrotron is currently being built at Monash's Clayton campus and is scheduled for completion in 2007.
Dr Whisstock's group was the first to find serpins in bacteria. In humans, mutations in serpins can disrupt the normal folding of these proteins or cause them to form inactive clumps. This leads to the development of diseases such as emphysema, liver cirrhosis, certain dementias and thrombosis.
Understanding the molecular basis of such degenerative disease processes is the major focus of a $6.5 million National Health and Medical Research Council program grant that has just been awarded to Dr Whisstock and his colleagues.
Dr Whisstock says such a project would not have been attempted without the PCU. "You don't think of this sort of research as being feasible without a crystallography unit being on your doorstep.
"Much of the research our team performs relies heavily on structural biology, and the interactions with the PCU are tremendously important."
Dr Rossjohn says structural biology within Monash is developing rapidly, and with the synchrotron based at Monash its future looks even brighter.
Action: For more information, visit Dr Jamie Rossjohn's website.