Crystallized alternative DNA structure sheds light on insulin-diabetes link

The first crystal structure of an alternative DNA form of the insulin gene has been revealed by a UCL-led research team.

It is commonly accepted that DNA is made up of two strands that wrap around each other, called a double helix, but it is possible for DNA to change shape and structure. The new study, published in Nature Communicationsreveals details of the structure of a type of DNA called i-motif by crystallizing it for the first time.

Co-lead author Dr Zoë Waller (UCL School of Pharmacy) said: “DNA is our genetic material and its structure typically resembles a twisted ladder called a double helix. This shape is iconic, but other DNA structures exist and are thought to play a role in the development of genetic diseases, such as diabetes or cancer.”

The researchers focused on i-motif DNA, which has a nested, knot-like structure and was only confirmed to exist in living human cells in 2018.

Dr Waller said: “It was already known that there was a region of DNA in the insulin gene that could fold into different DNA structures and shapes. It was also known that this region of DNA varied from person to person. Our work shows that these different sequence variants fold into different DNA shapes.”

The scientists used a crystallography technique that concentrates a solution containing DNA, allowing crystals to form, which is an important method for researchers to see the structure of DNA using X-ray crystallography.

Dr Waller explained: “We were able to crystallise a four-stranded DNA structure, called the ‘i-motif’. Our crystals allowed us to determine exactly what the structure of this DNA looks like using X-rays. This revealed that some DNA sequences have additional special interactions that help them form alternative DNA structures more easily.”

The research team demonstrated that different sequence variants in the insulin gene form different DNA structures, which in turn could affect whether insulin is activated or deactivated.

By demonstrating how the shape of DNA can affect the function of the insulin gene, already known to be essential in diabetes, they hope their findings could guide future research into diabetes treatment.

The crystal structure developed by the scientists may enable computational drug discovery to target the insulin gene’s i-motifs, because when scientists know the specific 3D shape, they can digitally design molecules and model them to see if they will fit.

Scientists can then develop new drugs using particular chemicals once they know which ones will work best for the drug’s target – a process called rational design.

As the first crystal structure of its kind, the researchers say it will also be useful as a model for other targets in the genome, besides the insulin gene, that form this form of DNA.

Dr Waller added: “This research means we can now use the shape of DNA to design molecules to bind these structures, which could be developed into drugs and potentially medicines.”