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Biomolecular Research Institute

Melbourne, Australia

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Biomolecular Research Institute, November 1999

Protein structure analysis at Parkville dates back to the 1950s, with Bruce Fraser and Tom MacRae using X-rays and, later, Peter Tulloch using electron diffraction to study natural fibers. However, the laboratory took a substantial new direction in 1978 when Peter Colman joined what was then the CSIRO Division of Protein Chemistry to set up protein crystallography. Peter brought with him some of the first crystals of influenza neuraminidase and, with the help of Bert van Donkelaar, began trying to determine the structure of this protein. Jose Varghese joined the laboratory in 1981 as a postdoctoral fellow and, by 1983, the structure of neuraminidase had been solved. This was a landmark in protein structure determination as it was large for its day and it was the first protein structure to be solved by averaging density from different crystal forms. Furthermore, the structure was solved without the use of computer graphics and most of the computation was performed remotely in Canberra.

In 1983 the possibility of using the neuraminidase structure to develop antiviral compounds was suggested and, after Glaxo showed only tentative interest, Biota Holdings was floated in 1985 to support the development of neuraminidase inhibitors in conjunction with the Victorian College of Pharmacy. From the structures of the protein with transition state analogues, a number of neuraminidase inhibitors were synthesised. Glaxo developed one of these compounds as the drug, Relenza, which has gone on sale this year. Other structure work in the 80's included electron and X-ray crystallography of neuraminidase-Fab complexes by Peter Tulloch and Bill Tulip, respectively, single crystal studies of a plant virus and structure determination of a seed storage protein by Mike Lawrence who joined the group in 1988.

In 1990, following a recommendation from a working party of the Victorian State Government, the Biomolecular Research Institute was formed with Peter Colman as Director. With structural biology at its core, BRI incorporated a novel idea of combining virology, biochemistry and organic chemistry, in addition to providing an integrated approach to structure-based drug design. The structure group diversified, drawing some staff from CSIRO and hiring others, such as Brian Smith, Vidana Epa (theoretical chemistry and modelling) and Tom Garrett (X-ray crystallography). BRI also added an NMR group.

The focus of the work is on proteins of medical interest and X-ray structures have been determined to understand infection by viral and bacterial pathogens as well as diseases such as diabetes, cancer, auto-immunity and allergies. Other areas of interest are growth factors, antibodies (including engineered smaller, single-chain forms), carbohydrate processing enzymes and engineering protein thermostability. Having an emphasis both on basic research and on its application, a number of projects have now been taken through to the stage of drug design and synthesis. A thermostable enzyme has also been produced for the brewing industry.

The X-ray instrumentation consists of Elliot, Siemens and Rigaku rotating anode generators and four image plate detectors. In addition, Jose and Bert have been helping develop capillary optics with David Balaic and Zwi Barnea from Melbourne University. These optics are particularly suitable for small crystals (<100micron) where increases in diffraction intensities by over a factor of 20 have been observed. As well as those mentioned above, the crystallography group consists of Mei Lou, Pat Pilling (crystallisation); Jenny Carmichael, Lin Chen, Ross DeGori, Robyn Malby (crystallography); Lyn Lawrence (electron microscopy) and Rob Downes (instrumentation). Adrian Batchelor has a joint appointment with the Walter and Eliza Hall Institute to work on structural aspects of malarial proteins. Recent past PhD students include Joao Barbosa, Tina Izard, Airlie McCoy and Kelly Maxwell.

Last year, and with great sadness, we mourned the loss of Peter Tulloch.

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