ShanghaiTech scientists resolve the structure

SHANGHAI, CHINA – September 15, 2022 – A team of scientists led by the iHuman Institute of ShanghaiTech University has determined and analyzed the cryo-electron microscopy structures of human bitter taste receptor TAS2R46 complexed with G protein, in both strychnine-bound and apo forms , providing the first three-dimensional image of human taste receptor. This study was published as the research article in the latest issue of Science.

The research team disclosed several features of TAS2R46, including distinct receptor structures that compare with known GPCRs, a new “toggle switch”, activation-related motifs, and precoupling of mini-G protein gustducin. At the same time, the team also revealed the binding mode of strychnine in TAS2R46. Strychnine is a toxic bitter alkaloid extracted from the seeds ofStrychnos nux-vomica and is used as an herb in traditional Chinese medicine to treat dyspepsia and pain.

By comparing the conformational changes between apo and strychnine-bound structures, researchers found the extracellular part of TAS2R46 is dynamic while the intracellular part is more static. Additionally, a new toggle switch residue Y2416.48T was identified for TAS2R46 activation. These features suggest the possible diverse ligand-recognition and activation process of TAS2R46.

“The 3D structures provide a basis for further exploration of other bitter taste receptors and their therapeutic applications.” said Prof. Zhi-Jie Liu, one of the corresponding authors of the paper, Executive Director of iHuman Institute.

Prof. Tian Hua, the other corresponding author, added “More importantly, bitter taste receptors display low sequence identity (<20%) with other GPCRs and are classified as a separate class T GPCR subfamily, which is the last structureless class of GPCRs . This study provides insights into the molecular features of class T GPCRs and improve our understanding of the whole GPCR family. I hope our study will help people understand the biology behind bitter taste perception and signaling. "

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