Structural basis for strychnine activation of human bitter taste receptor TAS2R46

Taste sensing is a sophisticated chemosensory process, and bitter taste perception is mediated by type 2 taste receptors (TAS2Rs), or class T G protein–coupled receptors. Understanding the detailed molecular mechanisms behind taste sensation is hindered by a lack of experimental receptor structures. Here, we report the cryo–electron microscopy structures of human TAS2R46 complexed with chimeric mini–G protein gustducin, in both strychnine-bound and apo forms. Several features of TAS2R46 are disclosed, including distinct receptor structures that compare with known GPCRs, a new “toggle switch,” activation-related motifs, and precoupling with mini–G protein gustducin. Furthermore, the dynamic extracellular and more-static intracellular parts of TAS2R46 suggest possible diverse ligand-recognition and activation processes. This study provides a basis for further exploration of other bitter taste receptors and their therapeutic applications. Bitter, sweet, and umami tastes are transduced by G protein–coupled receptors (GPCRs). The taste receptor type 1 (TAS1R) family has three members that combine to sense sweet and umami tastes, and a distinct type 2 family (TAS2R) facilitates the perception of bitter tastes. Xu et al . determined the structures of the human bitter taste receptor TAS2R46 bound to a mini–G protein containing the TAS2R46-binding site from the G protein gustducin. The structures reveal distinct features of TAS2R46 compared with other GPCRs and provide insight into how ligands such as the bitter alkaloid strychnine activate this GPCR to evoke a bitter taste. —VV A structure reveals insights into how a human bitter taste receptor recognizes a ligand and transduces the signal.