New Lipid-Bilayer Nanodiscs to Study GPCR Signalling

Membrane proteins are the doors and windows of biological cells, as they enable cellular communication and material transfer. These proteins make up about half of all drug targets, but their investigation in the laboratory is hampered by their generally poor stability once they have been removed from their cellular environment. Traditional methods used for isolating membrane proteins often depend on aggressive chemistry and result in protein destabilisation. Recently, some polymers (which are more widely known from plastics materials) have been shown to extract membrane proteins along with their lipid environment in a gentler manner to form so-called nanodiscs, that is, disc-shaped nanoparticles. These nanodiscs retain the native-like environment of extracted membrane proteins but, at the same time, allow their study under defined conditions. This international project aims at developing new polymers that combine good protein yields with favourable physicochemical properties such as to preserve the native structures, dynamics, and functions of labile membrane proteins. Our prime targets are so-called G protein-coupled receptors (GPCRs), which play key roles in numerous physiological processes ranging from appetite regulation to the sense of smell and which constitute the largest class of drug targets. With the aid of our new polymers, these proteins will be extracted from cellular membranes together with their surrounding lipid molecules to form polymer-encapsulated nanodiscs. These improved nanodiscs will retain the native structures, dynamics, and functions of the extracted proteins and, thereby, render them amenable to detailed investigation under well-controlled laboratory conditions.

Making membrane proteins accessible for research: a breakthrough in gentle protein isolation Membrane proteins are essential for life. They act as the "doors and windows" of our cells, controlling what enters and exits and enabling communication between cells. Because they play key roles in many physiological processes-from how we sense smells to how our bodies regulate hormones-they are among the most important drug targets. In fact, around half of all modern medicines act on membrane proteins. Despite their importance, studying membrane proteins in the lab has always been difficult. Once removed from their natural environment-the protective lipid layers of the cell membrane-they tend to lose their shape and function. Traditional extraction methods often involve harsh chemicals that damage these delicate proteins, making them unsuitable for detailed investigation. This project set out to solve this problem by developing a new class of polymers that gently extract membrane proteins while preserving their natural environment. These polymers, originally inspired by materials used in plastics, have been fine-tuned to stabilize membrane proteins and keep them functional outside the cell. Our research has successfully led to the creation of improved polymer-encapsulated nanodiscs-tiny disc-shaped structures that hold proteins together with their surrounding lipid molecules, mimicking their native conditions. A key achievement of our work was the development of nanodiscs that offer a better balance between protein stability and ease of handling. These new nanodiscs allow researchers to study fragile membrane proteins under well-controlled laboratory conditions, opening new possibilities for drug discovery and biomedical research. Our efforts focused particularly on G protein-coupled receptors (GPCRs), which are involved in processes ranging from taste perception to brain signaling and are among the most important targets in pharmaceutical development. The impact of these findings is far-reaching. By making membrane proteins more accessible for research, our methods could accelerate drug development, improve our understanding of disease mechanisms, and lead to better treatments for conditions such as neurological disorders, metabolic diseases, and even cancer. This project has brought us a step closer to unlocking the full potential of membrane proteins for science and medicine.