Bile acids are amphipathic molecules that synthesized from cholesterol in liver and further diversified by the gut microbiota. In addition to the emulsification of lipid soluble nutrients to facilitate digestion, the diverse bile acids are versatile hormones regulating a wide array of immune and metabolic processes. Playing a central role in the liver-bile acids-microbiota axis, bile acids and their receptors are the research hot spot in biomedical fields. Many research demonstrated that bile acids and their derivatives might be used to treat diseases like primary biliary cholangitis (PBC), non-alcoholic steatohepatitis (NASH), type 2 diabetes, et al.

Bile acids exert regulatory functions by activating the membrane receptor GPBAR/TGR5 and the nuclear receptor FXR. GPBAR belongs to the G protein-coupled receptor (GPCR) superfamily. Many of the beneficial effects of bile acids, such as protecting against obesity and diabetes, combating steatosis and reducing inflammation, have been attributed to GPBAR–Gs coupling. In addition, GPBAR signals to β-arrestin to induce innate antiviral immune response.

However, a number of adverse effects related to GPBAR activation leads to the suspend of drug development targeting GPBAR. Understanding at molecular level that how GPBAR recognizes so many different bile acids and how to induce downstream signaling bias will greatly facilitate our understanding of this receptor, and promote future drug discovery.

Recently, a group of Chinese scientists determined for the first time the 3? cryo-EM structures of the GPBAR–Gs in complexes with P395 and INT-777, a highly potent synthetic agonist and a semisynthesized bile acid derivative.

With the structural information and the biochemical assays, scientists revealed how GPBAR recognize amphipathic molecules and disclosed a finger print of amino acids used for the recognition of various bile acids. Besides, they discovered a second binding pockets for allosteric bile acid binding and elucidated a non-classical activation mechanism of GPBAR and the previous unclear function of ICL3 of GPCRs. In addition, they demonstrated the structural basis of biased signaling elicited by different ligands.

In conclusion, this research not only revealed the structural basis of GPBAR-bile acids recognition and signaling bias, but also discovered a unique activation mechanism which is different from all GPCRs with known structures. Considering the diverse and the important roles of GPBAR and bile acids in regulating metabolic and immune responses, the high-resolution structures of GPBAR-ligand-Gs complexes may greatly facilitate rational drug design and discovery targeting GPBAR.

Prof. ZHANG Yan from Zhejiang University, Prof. XIE Xin from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Profs. YU Xiao and SUN Jinpeng from Shandong University conducted this research, which was published online in Nature on July 22 with the title of “Structural basis of GPBAR activation and bile acid recognition”.

Link to the article: https://www.nature.com/articles/s41586-020-2569-1

Contact:
Prof. XIE Xin
E-mail: xxie@simm.ac.cn