A new study, led by by scientists at Saint Louis University determines the structure of a key protein that is involved in the body’s inflammatory response. The finding, published in Nature Communications, 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.

Sergey Korolev, associate professor of biochemistry and molecular biology at SLU, studies protein structures at the atomic resolution level to understand mechanism of their function in the body. Korolev says that the protein kept popping up in seemingly unrelated areas of study throughout the last few decades.

Korolev and his team examined calcium-independent phospholipase A2β, (iPLA2β) that cleaves phospholipids in membrane. It produces important signals after injury to initiate the inflammatory response. The team wanted to know how the enzyme is activated during injury, how it hydrolyses substrates and how it gets shut down, turning the inflammatory response off.

Researchers saw that the protein played different roles in different tissues and parts of the cell. The protein's changeable roles added to difficulties in understanding how it operated. 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.

In order to learn more about the protein's molecular structure, SLU researchers used x-ray crystallography to gather data. 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 in order to detail the three-dimensional structure of the protein. Often, the most difficult part of the process protein crystallization, which can take years to achieve.

"We've opened up lots of possibilities. The mechanism of regulation was completely unknown. Now, the 3D structure gives us a clear hypothesis for how it is responsible for action in different cellular compartments and tissues," Korolev said. "Now that we can better understand how the protein interacts with lipid molecules, it will be much easier to develop drugs."

"One of the key findings about the structure we uncovered is that it significantly revised previously developed theoretical models, which couldn't explain many functional features. Now, with the real structure, many pieces of an intricate puzzle click together providing clear hypothesis about the mechanism of protein's function and regulation."

In addition, 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.

"In the past, people have studied this complex enzyme, like a black box, without knowing what is inside," Korolev said. "Now that we have discovered the structure, we can see every atom. This allows us to visualize what is happening with this protein. It is a completely new level of insight."

"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," said Konstantin Malley, M.D./Ph.D. student, and he authored the paper. "We 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.

"We hope that it provides a jumping-off point for firstly, understanding how iPLA2β works in the brain. Next we 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."