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              Scientists Reveal Structural Basis of Bile Acid Receptor Activation and Ligands Recognition

              Jul 23, 2020

              Playing a central role in the liver-bile acids-microbiota axis, bile acids and their receptors are the research hot spot in biomedical fields. Studies have 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.
              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 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.

              In a study published online in Nature on July 22, Prof. ZHANG Yan from Zhejiang University, Prof. XIE Xin from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, and Profs. YU Xiao and SUN Jinpeng from Shandong University, determined for the first time the 3 angstrom 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. GPBAR expands a large ovate pocket to accommodate the bulky bile acids. The TM5, ECL2 and ECL3, form a hydrophobic wall which interact with the hydrophobic core of bile acids, while the hydrophilic side of bile acids form specific interactions with hydrophilic amino acids on TM6 and TM7.

              Meanwhile, scientists elucidated how amino acid finger prints recognizing various bile acids. Endogenous bile acids have the same core but are differentiated mainly by hydroxylation at various position. By analyzing the binding mode of INT-777 with GPBAR, they revealed that triplet leucine cluster (L2446.55, L2637.36 and L2667.39), as well as a potential role of S2476.58, constitute a fingerprint reader to discriminate the interactions between different bile acids and GPBAR.

              Besides, a second binding pocket for allosteric bile acid binding was discovered. Allosteric binding pockets are commonly discovered in GPCRs, but an allosteric binding pocket for native ligand is very unusual. Scientists discovered that the intracellular side of TM3-5 of GPBAR form a second bile acid binding pocket, and many bile acids with 12-OH structure could bind to this pocket and regulate receptor activation with ligand in the orthosteric pocket. This may explain the diverse functions of diverse bile acids, and provide novel insight to future drug design.

              In addition, scientists elucidated a non-classical activation mechanism of GPBAR and the previous unclear function of ICL3 of GPCRs, and demonstrated the structural basis of biased signaling elicited by different ligands.

              This study 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.

               

              Sensing Bile Acids (Image by SIMM) 

              Structural basis of GPBAR activation and bile acid recognition

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