A team of Australian scientists from CSIRO and the Biomolecular Research Institute has achieved a world-first advance by describing the structure of a vital receptor found on the surface of the body cells of all animals including humans.
The discovery, reported in this week's issue of the international scientific journal Nature, has major implications for our understanding of the mechanisms behind growth and development, and diseases such as diabetes and many forms of cancer.
The breakthrough, which is receiving international acclaim, was made by a team led by Dr Colin Ward of CSIRO Molecular Science and crystallographer Dr Tom Garrett of the BRI in Melbourne. The diabetes aspect of the work was funded in part by Biota Diabetes Pty Ltd, a wholly owned subsidiary of Biota Holdings Limited, and the Federal Government's AusIndustry program. The Managing Director of Biota, Dr Hugh Niall said "We are delighted to be associated with this discovery. It represents an advance in our joint diabetes program with CSIRO and the BRI, and has significance also for other important areas of biology and medicine."
The team's goal is to understand the atomic structure of a particular family of receptors, sites on the cell surface which detect chemical messengers such as insulin, IGF (or insulin-like growth factor) and EGF (epidermal growth factor), Dr Ward says.
Receptors are vital links in the body's command chain. Messenger chemicals like hormones and growth factors attach and switch on their special receptor, which in turns commands the cell to perform particular tasks, such as to grow or to process sugar.
The team is the first in the world to clarify the structure of half of the IGF receptor, marking a major scientific milestone in a field of research that has been running since the late 1960s when the 3D structure of insulin was determined.
"The IGF, insulin and EGF receptors are all in the same family and their structures are expected to be 90 per cent similar - so understanding the crystal structure of the IGF receptor helps us to understand most of the structure of all three," Dr Ward explains.
"IGF is important to the body's normal growth and development - but when it gets out of control it can also cause the growth of cancer cells. We hope this work in time will lead to a better understanding of ways to control certain cancers. This is a milestone in that process - but there is still a long, long way to go."
The Australian work took place at the most minuscule level - the team's target was a molecule which is only ten billionths of a metre long.
To understand the IGF receptor's structure, large quantities of the receptor fragment were produced in animal cells and purified to a very high level. The next step was to grow crystals from this material, much like salt crystals growing in a saline solution. The big difference is that the team's target crystal has over 7,000 atoms, whereas salt has just two.
The crystals were then bombarded with X-rays, yielding diffraction patterns. A powerful computer was then used to construct an image of the receptor from the diffraction data. From this Dr Garrett was able to work out the location of each atom in the receptor and build a three dimensional structure for this protein molecule.
"It's like a giant jigsaw puzzle. Piece by piece, we're slotting it together," Dr Ward says. "There has been plenty of excitement from our colleagues round the world about this discovery because it is the first glimpse of that part of the receptor which binds the hormone. It's been a long time coming."
Three years ago a US team clarified the structure of the portion of the receptor that lies inside the cell. The Australians have now described the structure of half of the receptor that lies outside, on the cell surface.
"The next step is to get the whole thing because the remaining parts of the receptor are also important for binding and biological action - and that should tell us a lot more about how these important chemicals communicate with the body. That, in turn, will help us to manipulate their effects and, hopefully, treat diseases like diabetes and cancer more effectively," said Dr Ward.
Journal
Nature