Two Key Transient Enzyme Complexes Analyzed

In a new research, an international team of experts was able to conduct in-depth analysis of the atomic structure of two key transient enzyme complexes in the human complement system. This system, as the name implies, complements the function of the body's natural defense, the immune system.

It represents an evolutionarily old branch of the immune response, and can be seen manifesting itself in most living things, from sponges to human beings. It works tremendously fast, by augmenting the work of antibodies in the immune system.

The main goal here is destroying foreign pathogens, such as bacteria and viruses, and the way the complement system assists in doing so is through a complex network of proteins.

With this study, experts were able to understand the system better, by analyzing two key transient enzyme complexes that underlie its rapid action. Details of the investigation appear in the December 24 issue of the top journal Science.

Two research groups collaborated to analyze the complexes. The first, at the University of Pennsylvania, was led by the Dr. Ralph and Sally Weaver Professor of Research Medicine, John Lambris, PhD.

The second, based at the Utrecht University, was led by expert Piet Gros. Together, the team was able to gain new insight into the enzymes' atomic structure. The research may help researchers design better drugs in the future.

“Now we will be able to design specific complement inhibitors to target this complex and in that way inhibit activation of the complement cascade, because now we know which parts of the proteins are essential for activity,” Lambris explains.

One of the main functions of complement proteins is marking bacterial and dying host cells for elimination from the body. The cellular clean-up “service” then removes everything that is tagged.

Previous studies have tied the action of these proteins with more than 30 conditions, such as myocardial infarction, stroke, and macular degeneration in the eye.

According to the team, the two analyzed complexes, called C3bB and C3bBD, play a pivotal role in amplifying the defense response by complement proteins. Both of them were analyzed using an observations technique called x-ray crystallography.

“Besides shedding light on a highly elegant mechanism of concerted activation and intrinsic regulation, this work also offers a detailed insight into one of the most important therapeutic targets within the complement network, which may facilitate rational drug development and could lead to novel drugs for treating complement-related diseases,” Lambris concludes.