Endocannabinoid System and Cannabinoid Receptors

The endocannabinoid system is an important endogenous system in human body that acts as a regulator to keep human homeostasis. Cannabinoid receptors, as the key components of this system, play roles in immunomodulation, appetite, memory and pain sensation. The two major cannabinoid receptors CB1 and CB2 are expressed predominantly in the central nervous system and the immune system, respectively. Their ligands, including agonists and antagonists, can be used for treatment of pain, mode, neurodegenerative disease, obesity, liver fibrosis, inflammation and immune diseases. Since 2016, we have disclosed the mysterious features of both CB1 and CB2 at inactive, intermediate and activated signaling states by structural biology studies. Further structure and pharmacology studies on the human cannabinoid receptors are ongoing, as well as the drug discovery targeting on the two receptors.  In addition, we are also interested in some orphan GPCRs that are related to endocannabinoid system and may be potential cannabinoid receptor candidates.

Neurological and metabolic diseases related GPCRs

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and contain 826 members in human bodies. They convey extracellular signals into the cell by activating intracellular processes such as heterotrimeric G protein-dependent signaling pathways. With at least 30% of marketed drugs being GPCR modulators, they are major therapeutic targets in the pharmaceutical industry’s drug discovery programs. A variety of GPCRs are widely distributed in the central nervous system (CNS), and mediate key physiological processes including cognition, appetite and synaptic transmission. In our lab, we are particular interested in the structure and function studies of GPCRs that closely related to the neurological and metabolic diseases. In the past years, we have determined the 3D structures of 5-HT2C serotonin receptor (5-HT2C), glucagon-like peptide-1 receptor (GLP-1R) and cannabinoid receptor CB1 and CB2.
In addition, some orphan GPCRs are highly expressed in the central nervous system and associated with CNS diseases. They are thought to be the new drug targets or modulator of some well-known target receptors. We are also focusing on determining the 3D structures of the related orphan GPCRs by cryo-EM and X-ray crystallography methods, exploring the receptors’ physiological function relationship with other GPCRs and trying to decipher the mechanism of orphan GPCRs in CNS diseases development.


Cryo-Electron Tomography for the Structure and Organization         Inside the Cell

How does the complex interior of the cell work? It's not just that one protein is doing its job, it's that proteins are working together to perform complex physiological tasks. Research on the structure and organization of proteins at the subcellular level is currently leading the way in cryo-electron tomography (cryo-ET). Cryo-ET can solve the three-dimensional reconstruction of the large complex inside the cell, such as cytoskeleton, nuclear pore complex, etc., providing new evidence for the exploration of protein function. This technology is currently in the development stage, and we hope to continue to improve the optimization of experimental conditions and technical methods to solve GPCR related issues.