A team of CSIRO scientists has determined the molecular structure of the insulin receptor, the protein on the surface of cells that mediates the effects of insulin. This advance builds on many years of international research to understand how insulin functions in the body.
Dr Colin Ward of CSIRO Molecular and Health Technologies and his team have been working on this problem since the early 1990s. The prestigious international journal Nature reports today on the discovery which is sure to lead to further important developments in the ongoing quest to understand the complexities of insulin’s actions.
This is firstly a great scientific achievement as the challenge of solving this structure has thwarted many laboratories world-wide over the last two decades. Secondly this discovery will facilitate future research that ultimately might lead to investigations into new therapies for diabetes or cancer.
Dr Ward says: “This is a landmark achievement, a bit like running the four minute mile. It follows on from the discovery of insulin in 1922, the determination of its amino acid sequence in the early 1950s and the determination of the 3D structure of insulin in 1969, each of which involved Nobel Prize winners.
“The receptor was discovered in 1969 and its amino acid sequence determined in 1985 but attempts to solve its 3D structure have been unsuccessful until now. It’s very exciting that our team has finally established what the receptor looks like.”
The approach taken to this research is known as structural biology. The protein of interest is grown in cells and then isolated, purified and crystallised. The crystals are then bombarded with beams of X-rays and data about the protein’s make-up is gradually assembled and interpreted until a full picture of the structure emerges.
This same approach was used by CSIRO scientists to determine the structure of an important protein on the surface of the influenza virus which led to the development of Relenza™, the world’s first drug to combat all strains of flu.
Dr Graeme Woodrow, the Chief of CSIRO Molecular and Health Technologies says: “This team has been at the forefront of research on the structural biology of the insulin receptor family for a long time and with their collaborators at the Ludwig Institute for Cancer Research and the Walter & Eliza Hall Institute of Medical Research, were the first to publish important structures from the structurally related epidermal growth factor receptor family of proteins. To beat other research teams to this discovery as well, speaks to the quality of Australian science.”
The immediate goal now is to obtain high resolution data on the insulin/insulin receptor complex and to extend this work to the closely related insulin-like growth factor (IGF) and the IGF receptor system, which is known to be important in cancer.
Dr Ward says: “The challenge for the future is to understand how insulin or IGF binding to their receptors triggers off cellular events that regulate the body’s uptake and utilisation of sugar or stimulate unregulated cell growth.
“When we know this we may be able to exploit this information to develop new treatments, but that is a long way off into the future.”
Images: jpg files of computer representations of the molecular structure of the insulin receptor Vision opportunities: Assorted lab shots, animated representations of the molecule, discussion of action of the receptor using a 3D model - Available from CSIRO Media.
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