CONCLUSION: Our cryo-EM structures reveal how fatty acid hormones bind the orthosteric site within the 7TM domain of GPCRs and how specific aromatic residues inside the ligand pocket recognize the C-C double bonds. We also investigated mechanisms underlying signaling bias of GPR120 in response to various ligands. This work will serve as a foundation for the development of molecules that bind and activate GPR120 for potential therapeutic uses as well as to better understand how ligand-induced conformational changes bias signaling outcomes in GPRCs.
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