Abstract：
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.
摘要：
琥珀酸盐,柠檬酸循环中间，在能量稳态和代谢调节中起着重要的作用。胞外琥珀酸通过琥珀酸受体（SUCNR1）充当应激信号，A类G蛋白偶联受体。由于缺乏激动剂结合的受体的高分辨率结构，因此阻碍了对琥珀酸信号传导的研究。我们介绍了与琥珀酸酯及其非代谢物衍生物顺式环氧琥珀酸酯结合的SUCNR1-Gi复合物的低温电子显微镜（cryo-EM）结构。识别顺式构象琥珀酸的关键决定因素包括R2817.39和Y832.64，而Y301.39和R993.29参与琥珀酸和顺式环氧琥珀酸的结合。胞外环2，通过其β发夹中的F175ECL2，与琥珀酸盐形成氢键并盖住结合袋。在受体-Gi界面，激动剂结合诱导跨膜(TM)5和TM6上疏水网络的重排,导致通过TM3和TM7的TM信号传导。这些发现扩展了我们对SUCNR1对琥珀酸识别的理解，有助于琥珀酸受体治疗剂的开发。
