In this study, researchers have determined the structure of a key protein that is involved in the body's inflammatory response. This finding opens the door to developing new treatments for a wide range of illnesses, from heart disease, diabetes, and cancer to neurodegenerative disorders, including Parkinson's disease. The studies on protein structures at the atomic resolution level to understand the mechanism of their function in the body.

Researchers examined a long-studied but little-understood enzyme, calcium-independent phospholipase A2β, (iPLA2β) that cleaves phospholipids in the membrane. It produces important signals after an injury to initiate the inflammatory response.

The team wanted to know how the enzyme is activated during injury, how it hydrolyzes substrates and how it gets shut down, turning the inflammatory response off. "It was first discovered more than 20 years ago at Richard Gross's lab," Korolev said. "They found that the protein played a role as a part of the cardiovascular system in response to ischemia or injury.

"Next, researchers found that it is also involved in the insulin production cycle and, when misregulated, can lead to type I diabetes. Then, less than ten years ago, it was rediscovered from a completely different point of view through the genetic sequencing of patients with neurodegenerative issues.

It was clear to scientists, though, that the action of the protein can be harmful, contributing to cardiovascular diseases, diabetes, and cancer metastasis, and many investigators attempted to design inhibitors to serve as potential new therapies. "Different groups tried to design inhibitors, but it was very difficult without knowing the 3D structure of the protein," Korolev said.

The process involves growing a crystal of the protein, shooting x-ray beams through the crystal and analyzing the diffraction pattern generated on a detector plate to detail the three-dimensional structure of the protein. Also, Korolev is intrigued by the protein's function in the brain, which is completely unknown.

Thanks to genetic sequencing, researchers can now map out which parts of a protein cause diseases. Having the genetic information together with the 3D structure will offer researchers a powerful new tool. "There is a growing amount of genetic work that links iPLA2β to neurodegenerative disease, and physicians and scientists worldwide are now interested in its function."

They are still a long way from treating patients, but I would like them to know that the structure is a large step between genetics and developing targeted therapies for treatment.

They hope that it provides a jumping-off point for firstly, understanding how iPLA2β works in the brain. Next they can employ different strategies, such as small molecule drugs, that would either prevent iPLA2β interacting with other proteins, or change its activity to prevent inflammation, which is an increasingly important factor in Parkinson's and other brain disorders.