Cell receptor dynamics and signaling

We study the dynamics and signaling of an important family of cell receptors, so-called G protein-coupled receptors (GPCRs), at the atomic level.

NMR spectroscopy captures the dynamic details in GPCR signaling.

G protein-coupled receptors (GPCRs) are a large family of membrane proteins crucial for cell signaling and the target of about 35 percent of all drugs. Despite that the knowledge of GPCRs has been advanced enormously in the last three decades, it remains as a puzzle of how natural ligands and synthetic drugs control GPCR signaling in the cell.

GPCR conformational dynamics
GPCRs are typically activated by binding of extracellular ligands, followed by coupling of intracellular transducer proteins (G protein, arrestin or other) to induce the signaling cascade inside the cell. We aim to capture the conformational dynamics of GPCRs during this activation process, to reveal the molecular determinants for GPCR ligand function, as well as the detailed coupling process between GPCR and G protein. To address the questions, we will use cutting-edge nuclear magnetic resonance (NMR) spectroscopy as well as other biophysical methods.

Most recently, we have developed a novel NMR technology, a method akin to designing a “global position system (GPS)” in the miniature protein system. This will allow us to visualize the conformational changes of GPCRs and their partner G proteins upon various ligands binding. Such observation will be achieved via following hundreds of labeled probes in the GPCR-G protein system.

Future better drug development
We will apply our method on several GPCRs, such as the well-known β1-adrenergic receptor. Our work will bridge the knowledge gap between the static GPCR structures and their function. The insights gained on ligand function and G protein coupling selectivity will be substantial for the future rational design of GPCR drugs with high specificity and high safety.