The initial crystal structure of a different DNA conformation from the insulin gene has been unveiled.
A research team from UCL has unveiled the first crystal structure of a non-traditional DNA formation associated with the insulin gene.
Typically, DNA is recognized as two strands twisted together in a shape called a double helix. However, DNA can actually adopt various forms and configurations. This fresh study, published in Nature Communications, highlights the structure of a DNA variant known as i-motif for the first time through crystallization.
Co-lead author Dr. Zoë Waller from UCL School of Pharmacy noted, “DNA serves as our genetic framework, and its conventional appearance resembles a twisted ladder, which we refer to as the double helix. Although this design is famous, other DNA formations exist and are believed to play a role in the emergence of genetic disorders, including diabetes and cancer.”
The research team concentrated on i-motif DNA, characterized by an interlocking structure similar to a knot, which was confirmed to exist in living human cells as recently as 2018.
Dr. Waller stated, “It was already known that a segment of DNA within the insulin gene can bend into various DNA shapes. Moreover, this DNA segment differs among individuals. Our research shows that these sequence variations lead to different DNA configurations.”
The scientists used a crystallography method that involves concentrating a solution with the DNA to facilitate crystal formation, a crucial technique that allows researchers to analyze DNA structures via X-ray crystallography.
Dr. Waller elaborated: “We successfully crystallized a four-stranded DNA formation known as ‘i-motif’. Our crystals enabled us to accurately determine the structure of this DNA through X-ray analysis, revealing that particular DNA sequences engage in unique interactions that allow them to form alternative structures more readily.”
The research group established that various sequence variants within the insulin gene generate differing DNA configurations, which could influence whether insulin is activated or deactivated.
By illustrating how DNA shape impacts the functionality of the insulin gene, which is essential for diabetes, the researchers aim for their discoveries to inform future diabetes therapies. The crystal structure created by the scientists may pave the way for computational drug discovery targeting the i-motifs of the insulin gene. Understanding the specific 3D structure allows scientists to digitally design molecules and predict their compatibility. Subsequently, they can develop new medications using specific compounds that are known to best fit the drug target, a method called rational design.
As the inaugural crystal structure of its kind, the team’s findings are anticipated to serve as a model for exploring other genome targets beyond the insulin gene that form this DNA shape.
Dr. Waller added, “This research enables us to utilize DNA shape to create molecules that can bind to these structures, with the potential for developing drugs and therapeutic solutions.”
This research was funded by Diabetes UK.
The UCL School of Pharmacy has a distinguished record in characterizing alternative DNA structures, starting from the first crystal structure of a distinct DNA formation known as G-quadruplex in a 2011 study, and continuing to establish in 2018 that the human telomere can create junctions.
