G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in our cells, involved in signal transmission across the cell membrane. One of the biggest questions is how a signal recognized at the extracellular side of a GPCR induces a sequence of conformational changes in the protein and finally evokes an intracellular response. EPFL scientists have now used computer modeling to reveal in molecular detail the structural transitions that happen inside GPCRs during the signal transduction process. They discovered that a central step in the trans-membrane signaling process is the formation of a continuous water pathway inside the G protein coupled receptors. The work, published in Nature Communications, proposes that future therapeutic compounds might be selected according to their potential to interfere with the receptors' internal waters. GPCRs amplify extracellular signals to finally evoke intracellular responses.

GPCRs are membrane proteins on the cell's surface. There are approximately 800 different GPCR types, each of which can detect and bind specific molecules on the cell's surface, which are called 'ligands'. Upon binding a ligand, the GPCR transmits a signal across the cell's membrane where specialized, so-called G proteins work to amplify the signal using a cascade of biochemical reactions that evoke cellular responses.

As these processes are of central importance for the proper function of our cells, even slight malfunctions of these processes can result in severe diseases. This makes GPCRs of utmost importance as targets for modern drug development, while a large proportion of current clinical drugs target various GPCRs. Therefore, understanding how GPCRs function at a molecular level can lead to the development of novel, powerful drugs for the treatment of diseases including cancer, diabetes, neurological disorders, inflammations, immunological disorders and cardiovascular disorders.

The 3D structures of a few GPCRs have already been solved by X-ray crystallography. However, this approach generates only static structures, which are not suited to uncover the structural changes that occur within the GPCRs during the signal transduction process.