Discovery Puts A Shape on Hormone Messages to Cancer Cells

August 2 '98 The structure of a receptor on the surface of the body cells of all animals including humans has been described for the first time. The discovery of the outer IGF receptor is likely to impact understanding of diabetes and many forms of cancer including prostate cancer.
     Receptors are vital links in the body's command chain. Messenger chemicals such as hormones and growth factors latch on to their pecial receptors and switch them on. This is how the messenger chemical command cells to perform vital tasks, such as to grow, or (in diabetes) to process sugar. Some new cancer therapies are targeted at receptors on tumor cells to block tumor access to growth factors fueling the metastatic cascade.
     This breakthrough, reported in July in the international scientific journal Nature, was made by a team of Australian scientists led by Dr Colin Ward, who studies molecules, and Dr Tom Garrett, a crystallographer
     Their goal, says Dr. Ward, is to understand the atomic structure of a whole 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)..
    This is the first time anyone has been able to view and describe this half of the IGF receptor. The research began in the late 1960s, when scientists figured out that insulin has a 3D structure.
     "As the IGF receptor is in the same family as the insulin and EGF receptors, their structures are likely to be extremely similar," says Dr Ward. "So this discovery has major implications for our understanding of the mechanisms behind growth and development, including some forms of cancer.... "
    "IGF is important to the body's normal growth and development," Ward says. "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 Australians' work took place at the most miniscule level. The team's target was a molecule which is only ten billionths of a metre long. To be able to examine the 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.

Dr. Colin Ward works for CSIRO (Commonwealth Scientific and Industrial Research Organisation) in Australia. Crystallographer Dr Tom Garrett works for the Biolmolecular Research Institute in Melbourne. Their work was published in July 23 issue of Nature:
Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor Garrett, TPJ et al

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See also "IGF-1: New Prostate Cancer Marker"

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