Researchers have made a discovery that could make therapeutic insulins more effective by better mimicking the way insulin works in the body. The findings could improve treatments for diabetes, a disease that impacts the lives of millions of people worldwide.
Published in Nature Communications, the study reveals the first definitive 3D image of how insulin successfully interacts with its receptor - a 'gatekeeper' for transmitting information into cells - in a process that is crucial for instructing cells to lower blood sugar levels in the body. Understanding exactly what this process looks like could inform the design of faster-acting and longer-lasting insulin therapies.
The researchers produced the first 3D image of how insulin binds to its receptor on the surface of cells in order to instruct the uptake of sugar from the blood.
The cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation.
The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises.
"We knew that insulin underwent a physical change that signalled its successful connection with its receptor on the cell surface. But we had never before seen the detailed changes that occurred in the receptor itself, confirming that insulin had successfully delivered the message for the cell to take up sugar from the blood.
"We then combined more than 700,000 of these 2D images into a high-resolution 3D image showing precisely what the successful binding between insulin and its receptor looks like. And there it was before our eyes, the full picture in exquisite detail.
https://www.wehi.edu.au/news/insulin-discovery-game-changer-improving-diabetes-treatments
https://www.nature.com/articles/s41467-018-06826-6
