Structural insights into ligand recognition and activation of the succinate receptor SUCNR1
Aijun Liu,
Yezhou Liu,
Weijia Zhang,
Richard D. Ye
Affiliations
Aijun Liu
Dongguan Songshan Lake Central Hospital, Dongguan Third People’s Hospital, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, Guangdong 523326, China; Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong 518000, China; Corresponding author
Yezhou Liu
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong 518000, China
Weijia Zhang
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
Richard D. Ye
Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China; The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen, Guangdong 518000, China; Corresponding author
Summary: Succinate, a citric acid cycle intermediate, serves important functions in energy homeostasis and metabolic regulation. Extracellular succinate acts as a stress signal through succinate receptor (SUCNR1), a class A G protein-coupled receptor. Research on succinate signaling is hampered by the lack of high-resolution structures of the agonist-bound receptor. We present cryoelectron microscopy (cryo-EM) structures of SUCNR1-Gi complexes bound to succinate and its non-metabolite derivative cis-epoxysuccinate. Key determinants for the recognition of succinate in cis conformation include R2817.39 and Y832.64, while Y301.39 and R993.29 participate in the binding of both succinate and cis-epoxysuccinate. Extracellular loop 2, through F175ECL2 in its β-hairpin, forms a hydrogen bond with succinate and caps the binding pocket. At the receptor-Gi interface, agonist binding induces the rearrangement of a hydrophobic network on transmembrane (TM)5 and TM6, leading to TM signaling through TM3 and TM7. These findings extend our understanding of succinate recognition by SUCNR1, aiding the development of therapeutics for the succinate receptor.
