Researchers get clear picture of cancer growth factor
Friday, 20 September, 2002
The crystal ball has cleared, and a Melbourne research team has seen one of the shapes of the future in cancer research, after solving the elusive structure of a receptor for a growth factor involved in many common cancers.
Researchers with the CRC for Cellular Growth Factors have produced the first three-dimensional images of a molecule known as the epidermal growth factor (EGF) receptor, a cell-surface molecule that proliferates on the surface of cancerous cells, turbo-charging their growth and replication.
Dr Colin Ward, of CSIRO Molecular Science, who headed the x-ray crystallography project to probe the receptor's structure, says the EGF receptor has been the model for studies of the interactions between receptors and their ligands since the 1980s.
Ligands are the signalling molecules that transmit information between cells, by 'docking' with receptor molecules on the surface of target cells. Ward says the EGF receptor is activated by at least five other molecules, that, despite their dissimilar chemistry, have the same basic, triangular shape as EGF itself.
The CRC's project involve researchers from CSIRO, the Walter and Eliza Hall Medical Research Institute, the Ludwig Institute for Cancer Research, and Molecular Science, CSIRO and the Melbourne-based pharmaceutical company Amrad.
Like many receptor molecules, the EGF receptor does its work as a 'twin', or dimer -- it becomes activated only after two identical EGF receptor molecules link up, and are activated by identical ligand molecules.
The big surprise, says Ward, is that the EGF receptors work back-to-back, like tango dancers twining their arms around each other backwards, rather than face to face.
This means that the two ligand molecules, instead of being held between the two receptor molecules, bind to the outside of the receptor complex, at the 3 o'clock and 9 o'clock positions.
Ward said this discovery is likely to be crucial to the design of anti-cancer therapeutics that will be custom-designed to mimic the native ligands, but will lack their activity -- by blocking and inactivate the receptor, these "dummy" molecules should switch off the growth of cancerous cells.
He said abnormal EGF activity was a feature of cancers of the head, neck, colorectal tumours, breast and ovarian cancers, and pancreatic cancer.
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