G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in our cells, involved in signal transmission across the cell membrane¹. 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 evokes⁴ an intracellular response. EPFL scientists have now used computer modeling to reveal in molecular⁵ detail the structural⁶ 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 therapeutic⁷ compounds might be selected according to their potential to interfere⁸ with the receptors' internal waters. GPCRs amplify⁹ extracellular signals to finally evoke³ intracellular responses.

 

GPCRs are membrane proteins on the cell's surface. There are approximately 800 different GPCR types, each of which can detect and bind¹⁰ specific molecules¹¹ on the cell's surface, which are called 'ligands'. Upon binding¹² a ligand, the GPCR transmits a signal across the cell's membrane where specialized¹³, so-called G proteins work to amplify the signal using a cascade¹⁴ of biochemical reactions that evoke cellular² responses.

 

As these processes are of central importance for the proper function of our cells, even slight malfunctions¹⁵ 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, diabetes¹⁶, neurological disorders¹⁷, 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.

点击收听单词发音