The succinate receptor SUCR1 is a potential therapeutic target for ulcerative colitis, liver fibrosis, diabetes, and rheumatoid arthritis. It plays a critical role in the regulation of mitochondrial reactive oxygen species homeostasis. Due to the lack of human SUCR1 structure, the mechanisms of succinate (SA) perception, receptor activation, and signal transduction by SUCR1 are still unknown.

In a study published in Cell Research on May 14, Prof. WANG Jiangyun's team from the Institute of Biophysics of the Chinese Academy of Sciences has resolved the structures of succinate-bound SUCR1-G_q and cis-epoxy succinate (ESA) bound SUCR1-G_i complexes using the single-particle cryo-electron microscopy technology.

Overcoming a series of challenges such as low ligand binding affinity and complex assembly difficulties, the researchers found that the extracellular loop 2 (ECL2) and the residue R99^3.29 play key roles in SUCR1 activation. The precise positioning of ECL2 is necessary for the formation of the functional agonist binding site.

Furthermore, structural comparisons of SUCR1-G_q and SUCR1-G_i revealed that the α5-helix of G_i and G_q have different orientations in the intracellular cavity of SUCR1, resulting in distinct interaction barcodes between SUCR1 and G_q or G_i proteins, explaining the mechanism of coupling selectivity of SUCR1 with downstream G proteins.

This study elucidates the molecular activation mechanism and G protein selectivity mechanism of SUCR1, which will promote the exploration of chemical sensing and drug design targeting succinate receptors.

The molecular activation and G protein selectivity mechanism of the succinate receptor. (Image by WANG Jiangyun's group)