Succinate is an intermediate of the citric acid cycle and serves important functions in energy homeostasis and metabolic regulation. Extracellular accumulation of succinate acts as a stress-induced signal through its G protein-coupled receptor, SUCNR1. Research on succinate signaling is hampered by the lack of high-resolution structures of the agonist-bound receptor. Here we present cryo-EM structures of SUCNR1-Gi complexes with the receptor bound to succinate and its non-metabolite derivative epoxysuccinate. Structural analysis of SUCNR1 identified key determinants for recognition of the dicarboxylate agonists in cis conformation. R2817.39 and Y832.64 are critical to ligand binding, but Y301.39 and R993.29 also participate in binding of succinate and epoxysuccinate, respectively. The extracellular loop 2, through F175ECL2 in its β-hairpin, forms a hydrogen bond with one of the carboxyl groups and serves as a lid to cap the binding pocket for succinate. At the receptor-Gi protein interface, agonist binding induces the rearrangement of a hydrophobic network on TM5 and TM6, leading to transmembrane signaling through TM3 and TM7. The agonist-bound SUCNR1 structures shed light on molecular recognition of succinate for receptor signaling, that may promote further development of novel agonists, antagonists and biased agonists targeting SUCNR1.

Structural insights into agonist binding and activation of succinate receptor 1