As crucial drug targets, G-protein-coupled receptors are responsible for the effectiveness of nearly half of all medicines prescribed today. GPCRs are integral membrane proteins that control and modulate the processing of sensory and physiological stimuli, such as those relevant to our sight and taste, or those involved in controlling our heart rate.

The aim of the research was to establish how G-protein-coupled receptors (GPCRs) and arrestin form complexes. Results from this research, which has been published in the journal Nature Communications, identify a previously unknown binding element critical to the arrestin - GPCR interaction.

Some of the side effects that occur with certain medicines (such as morphine-based drugs) are the result of arrestin-dependent signaling pathways. The researchers' close observation of the interactions between arrestins and GPCRs yielded crucial conclusions.

"We asked ourselves how these two proteins manage to find each other, and what happens when they come together to form a complex. The recent crystal structure of a GPCR-arrestin complex prompted us to ask whether a section of arrestin called the C-edge might interact with the membrane adjacent to the GPCR," explains the senior author.

Using a combination of computer simulations, and site-directed fluorescence spectroscopy, authors show that loops within the C-edge of arrestin binds to the membrane. Activation of arrestin by receptor-attached phosphates is necessary for C-edge engagement of the membrane, and authors show that these interactions are distinct in the pre-complex and high-affinity complex in regard to their conformation and orientation.

The existence of this type of interaction was previously unknown, and its discovery opens up a whole new field of research regarding how the membrane influences the function of arrestin.

A better understanding of GPCR-arrestin interactions is essential if we are to develop drugs with fewer side effects. The team have already begun to explore the role of the membrane on the structure and interactions inside the GPCR-arrestin complex.