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, or 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 cardiovascular disease, inflammatory illnesses like rheumatoid arthritis and multiple sclerosis, neurodegenerative diseases like Alzheimer’s, and multiple types of cancer.
Their involvement in a broad range of diseases makes GRKs an attractive drug target. Around 30% to 40% of all drugs currently on the market focus on these proteins. However, designing drugs that selectively target specific GRKs is a difficult task. Because they are structurally 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. So my work in the Tesmer Lab at Purdue University focuses on uncovering more information on the structure of GRKs.
What do G protein-coupled receptor kinases look like?
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.
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 Pac-Man – is the catalytic center where the protein does its main job: adding a phosphate group to 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.
The three domains of GRKs resemble a Pac-Man with a ponytail. Shown here is GRK2.
Priyanka Naik, CC BY-ND
The RH domain – the ponytail – stabilizes the kinase domain. It guides and docks the GRK to its target protein.
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…
