Understanding GRKs: The ‘Pac-Man with a Ponytail’ Proteins

Each cell in your body relies on precise communication with other cells to function properly. At the center of this process are the molecular switches that turn communication signals in the body on and off. These molecules are key players in health and disease. One such molecular switch is G protein-coupled receptor kinases (GRKs) for short. From vision to heart function and cell growth, GRKs play a vital role in maintaining physiological balance. When they go awry, they can contribute to various diseases, like rheumatoid arthritis, multiple sclerosis, and Alzheimer’s. Their involvement in a broad range of diseases makes GRKs an attractive drug target.

The Challenge of Targeting GRKs

Around 20 drugs currently on the market focus on these proteins. However, designing drugs that selectively target specific GRKs is a difficult task. Because they are similar to each other and to other proteins, molecules binding to one GRK might also bind to many other enzymes and cause unwanted side effects. A better understanding of how GRKs interact with their targets can help researchers develop better drugs.

Research at Purdue University

So in the lab at Purdue University, researchers focus on uncovering more information on the structure of GRKs. What researchers know about the structure of GRKs has advanced significantly over the past two decades, revealing the intricate mechanisms by which they function. The ability to physically look at proteins is highly useful for drug development. Seeing a protein’s structure is like looking at a jigsaw puzzle – you can find the missing piece by knowing its shape. Similarly, knowing a protein’s shape helps scientists design molecules that fit perfectly into it, making drugs more effective.

Structure of GRKs: The Pac-Man Analogy

GRKs consist of several modules, or domains, that serve a particular purpose. Together, these modules assemble into a structure resembling a Pac-Man with a ponytail. The kinase domain – the core of the protein – is the catalytic center where the protein does its main job: to phosphorylate its target to control its activity. It has two subdomains – one small and one large lobe – connected by a hinge that can open and close. Like Pac-Man, this domain closes around reactants and reopens to release products.

Diversity Among GRKs

Humans have seven GRKs, each specialized for different tissues and functions, and each unique in structure. Some regulate vision, while others affect your brain, kidney, and immune functions, among others. Their structural differences dictate how they interact with their targets, and understanding these distinctions is key to designing drugs that can selectively target each one.

Historical Discoveries in GRK Research

In 2003, researchers in the lab where I work uncovered the first known structure of a GRK – GRK2, which is involved in heart functions and cell proliferation – by using a technique called X-ray crystallography. This involved bombarding a GRK2 sample with X-rays and tracing where they bounce off to determine where each atom of the protein is located. By determining how the three modules of GRK2 are arranged and where its target molecules would bind, my colleagues and I can design drugs that strongly interact with GRK2.

Future Implications for Drug Development

For example, in 2012, one of my colleagues discovered that the antidepressant targeted GRK2 effectively, showcasing the potential for targeted therapies. As we continue to explore the structure and function of GRKs, the implications for drug development are immense. By unlocking the secrets of these ‘Pac-Man with a ponytail’ proteins, we can pave the way for more effective treatments for a variety of diseases.