Structural biology

Tremendous strides have been taken over the past twenty years in the understanding of biology and the processes that make life possible. Central to this has been the understanding of the role of genes, and the breaking of the DNA code. Recent unravelling of the human genome had led to the perception that this knowledge will help cure many intractable diseases, and the control and manipulation of biota is possible

Understanding the genome is important, but of greater interest in the post-genomic era is an understanding of the structure and function of the many proteins that are expressed by the gene. This is a very large undertaking-it is estimated that there are over one million different products compared to the 30000 genes that make up the human genome.

Thus a new field of proteomics has emerged that involves the systematic characterization of the gene products of entire organisms. Beyond proteins, there are other complex macromolecules of key importance in biological processes, such as viruses and nucleic acids.

The determination of the three dimensional structures of these complex macromolecules is known as structural biology. Perhaps the best-known technique employed by structural biologists is protein crystallography using single crystal x-ray diffraction, which provides the primary structural information; the crystal structure of the molecule. But knowledge of the crystal structure alone is insufficient; of equal and sometimes greater importance is the elucidation of the shape of the molecule and how it is folded. This is the secondary, or conformational, structure of the molecule.

Although nuclear magnetic resonance (NMR), mass spectrometry, and cryo-electron microscopy do provide valuable information on the primary and secondary structures of complex macromolecules, x-ray diffraction, small-angle scattering and circular dichroism are the key techniques used in structural biology.

Early attempts to analyse macromolecular structures used conventional x-ray and laboratory light sources; the most famous of these is probably the determination of the structure of DNA by Watson and Crick. However, it was not until developments over the past decade in cloning and over-expression of proteins, more effective methods of protein manipulation, cryogenic cooling of the crystals to minimize degradation by the radiating beam, advances in computer and detector technology and, in particular, access to synchrotron light that large-scale structural biology has been possible.

The growth in activity has been spectacular. A measure of this growth is the number of structures registered in the Protein Data Bank over the period spanning 1972 to 2002. The remarkable rise after 1992, in particular, coincides with the commissioning of a number of synchrotron-based protein crystallograpy beamlines. At 7 October 2003, the number of proteins registered in the bank was 22810, of which 19380 were determined by x-ray diffraction.

Australia has been a major player in proteomics-the term was coined by researchers at Macquarie University. Access to the protein crystallography, SAXS/WAXS and circular dichroism beamlines at the Australian Synchrotron will maintain the world-leading position of Australian researchers in this area.