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Synchrotron X-Ray Crystallography Generates Insulin-Insulin Receptor Binding Images

By BiotechDaily International staff writers
Posted on 24 Jan 2013
The light generated by a state-of-the-art particle accelerator was used to capture X-ray crystallographic images of the three-dimensional interaction between insulin and its receptor.

Insulin receptor signaling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation, and survival. Insulin resistance contributes to the development of diseases such as type II diabetes mellitus and Alzheimer’s disease. Abnormal signaling generated by cross talk with the homologous type 1 insulin-like growth factor receptor (IGF1R) occurs in various cancers. Despite more than thirty years of research, it has not been possible to document the three-dimensional structure of the insulin-insulin receptor due to the complexity of producing the receptor protein.

In a paper published in the January 9, 2013, online edition of the journal Nature an international research time described the use of the Australian Synchrotron to capture the three-dimensional structure of insulin bound to the insulin receptor.

The Australian Synchrotron (Clayton, Australia) is a light source facility that uses particle accelerators to produce a beam of high-energy electrons that are placed within a storage ring that circulates the electrons to create synchrotron light. The electron beams travel at just under the speed of light - about 299,792 kilometers per second, and the intense light they produce is filtered and adjusted to travel down separate beamlines to separate end stations where are placed a variety of experimental equipment including one for protein crystallography.

X-ray crystallographic images generated by the Synchrotron revealed the sparse direct interaction of insulin with the first leucine-rich-repeat domain (L1) of the insulin receptor. Instead, the hormone engaged the insulin receptor carboxy-terminal alpha-chain (alphaCT) segment, which was itself remodeled on the face of L1 upon insulin binding. Contact between insulin and L1 was restricted to insulin B-chain residues. The alphaCT segment displaced the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is thought to be novel within the broader family of receptor tyrosine kinases.

"We have now found that the insulin hormone engages its receptor in a very unusual way," said senior author Dr. Michael C. Lawrence, associate professor of structural biology at Walter and Eliza Hall Institute of Medical Research (Melbourne, Australia). "Both insulin and its receptor undergo rearrangement as they interact - a piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone."

"Understanding how insulin interacts with the insulin receptor is fundamental to the development of novel insulins for the treatment of diabetes," said Dr. Lawrence. "Until now we have not been able to see how these molecules interact with cells. We can now exploit this knowledge to design new insulin medications with improved properties, which is very exciting. Insulin is a key treatment for diabetics, but there are many ways that its properties could potentially be improved. This discovery could conceivably lead to new types of insulin that could be given in ways other than injection, or an insulin that has improved properties or longer activity so that it does not need to be taken as often. It may also have ramifications for diabetes treatment in developing nations, by creating insulin that is more stable and less likely to degrade when not kept cold, an angle being pursued by our collaborators. Our findings are a new platform for developing these kinds of medications."

Related Links:
Australian Synchrotron
Walter and Eliza Hall Institute of Medical Research



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