Structural basis of species-selective antagonist binding to the succinate receptor

Nature. 2019 Oct;574(7779):581-585. doi: 10.1038/s41586-019-1663-8. Epub 2019 Oct 23.


The tricarboxylic acid cycle intermediate succinate is involved in metabolic processes and plays a crucial role in the homeostasis of mitochondrial reactive oxygen species1. The receptor responsible for succinate signalling, SUCNR1 (also known as GPR91), is a member of the G-protein-coupled-receptor family2 and links succinate signalling to renin-induced hypertension, retinal angiogenesis and inflammation3-5. Because SUCNR1 senses succinate as an immunological danger signal6-which has relevance for diseases including ulcerative colitis, liver fibrosis7, diabetes and rheumatoid arthritis3,8-it is of interest as a therapeutic target. Here we report the high-resolution crystal structure of rat SUCNR1 in complex with an intracellular binding nanobody in the inactive conformation. Structure-based mutagenesis and radioligand-binding studies, in conjunction with molecular modelling, identified key residues for species-selective antagonist binding and enabled the determination of the high-resolution crystal structure of a humanized rat SUCNR1 in complex with a high-affinity, human-selective antagonist denoted NF-56-EJ40. We anticipate that these structural insights into the architecture of the succinate receptor and its antagonist selectivity will enable structure-based drug discovery and will further help to elucidate the function of SUCNR1 in vitro and in vivo.

MeSH terms

  • Animals
  • Apoproteins / antagonists & inhibitors
  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / pharmacology*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Piperazines / chemistry*
  • Piperazines / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Purinergic P2Y1 / chemistry
  • Signal Transduction
  • Single-Domain Antibodies / chemistry
  • Species Specificity
  • Succinic Acid / metabolism


  • Apoproteins
  • Biphenyl Compounds
  • Piperazines
  • Receptors, G-Protein-Coupled
  • Receptors, Purinergic P2Y1
  • Single-Domain Antibodies
  • Sucnr1 protein, rat
  • Succinic Acid