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TitleStructural insights into ligand recognition and activation of the succinate receptor SUCNR1.
Journal, issue, pagesCell Rep, Vol. 43, Issue 7, Page 114381, Year 2024
Publish dateJul 23, 2024
AuthorsAijun Liu / Yezhou Liu / Weijia Zhang / Richard D Ye /
PubMed AbstractSuccinate, a citric acid cycle intermediate, serves important functions in energy homeostasis and metabolic regulation. Extracellular succinate acts as a stress signal through succinate receptor ...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 R281 and Y83, while Y30 and R99 participate in the binding of both succinate and cis-epoxysuccinate. Extracellular loop 2, through F175 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.
External linksCell Rep / PubMed:38923454
MethodsEM (single particle)
Resolution2.97 - 3.15 Å
Structure data

37686

8wog

EMDB-37686, PDB-8wog:
Cryo-EM structure of SUCR1 in complex with succinate and Gi protein
Method: EM (single particle) / Resolution: 2.97 Å

37707

8wp1

EMDB-37707, PDB-8wp1:
Cryo-EM structure of SUCR1 in complex with cis-epoxysuccinic acid and Gi proteins
Method: EM (single particle) / Resolution: 3.15 Å

Chemicals

ChemComp-SIN:
SUCCINIC ACID

ChemComp-HOH:
WATER

ChemComp-U9S:
(2R,3S)-oxirane-2,3-dicarboxylic acid

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR / Succinate Receptor 1 / succinate receptor

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