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New discovery to help switch off disease

CSIRO : 28 January, 2003  (New Product)
A landmark discovery could lead to a host of new drugs that may contribute to 'switching-off' diseases such as cancer, osteoporosis and rheumatoid arthritis, and boost the immune system.
A group of Melbourne scientists has been able to draw a three dimensional map of a protein believed to be involved in the development of several human diseases.

'This is the vital first step to developing new ways to stop a disease in its tracks,' says CSIRO researcher, Dr Jose Varghese.

'Now that the structure has been determined we can begin to understand how it works, and therefore find ways to stop its processes.'

The same method was used to develop the 'flu drug, Relenza, which acts as a molecular 'plug' to prevent the virus from replicating, thereby shortening the duration of illness.

The protein, called the Interleukin 6 Receptor, is found on the surface of many types of cells. It binds specifically to a circulating hormone of the immune system called Interleukin-6.

'This interaction has been implicated in the development of multiple myeloma, post-menopausal osteoporosis, autoimmune diseases and prostate cancer,' Dr Varghese says.

'It is also involved in inflammatory diseases, in particular rheumatoid arthritis, and is thought to be involved in the development of some forms of cardiovascular disease.'

The group determined the three-dimensional atomic structure of the Interleukin-6 receptor by x-ray crystallography which involves growing a crystal from the pure protein and shooting an x-ray beam through it to generate the unique patterns from which a structure is determined. The Melbourne research team used a synchrotron facility in Chicago, USA.

They have also developed a theoretical atomic model of how the Interleukin-6 Receptor interacts with its hormone, Interleukin-6, the final piece in the jigsaw that shows how this may initiate the biochemical changes in cells that are sensitive to it.

Prof. Richard Simpson of the Ludwig Institute for Cancer Research says this work is a valuable addition to the current information regarding how the receptor and the hormone interact.

'Interleukin-6 also plays a central role in the body's defence system and has a wide range of immune activities in that it helps turn on antibody production and stimulates immune cell production and activation. It has a potent ability to induce many of the immediate biochemical changes associated with inflammation which results in changes to the levels of proteins involved in inflammation and which can contribute to the damaging effects of inflammation,' says Prof. Simpson.

'We hope that it will form the basis for the development of agents that have the ability to interfere with or augment the biological activity of Interleukin-6.'

This discovery is published in the Proceedings of the National Academy of Sciences (USA).

The discovery is the result of collaboration between CSIRO Health Sciences and Nutrition and the Ludwig Institute for Cancer Research, through the CRC for Cellular Growth Factors.

Dr. Jose Varghese of CSIRO and Prof. Richard Simpson of the JPSL (Joint ProteomicS Laboratory of the LICR and the Walter and Eliza Hall Institute of Medical Research) led the teams that made this discovery, utilising the protein isolation and purification facilities of the JPSL, and the cell-culture and protein crystallographic facilities at CSIRO.

Other research team members involved in this discovery were Robert Moritz and Dr Ji Hong of the JPSL, who were involved in the task of synthesizing the protein in a highly purified form to allow crystallization, and Kim Branson, a graduate student with Dr Varghese, who constructed the model of the complex.
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