6RNK

Crystal structure of a humanized (K18E, K269N) rat succinate receptor SUCNR1 (GPR91) in complex with a nanobody and antagonist NF-56-EJ40.

Summary for 6RNK

• Entry DOI: 10.2210/pdb6rnk/pdb
• Related: 6IBB
• Descriptor: Succinate receptor 1, Nanobody6, 2-[2-[[3-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]phenyl]carbonylamino]phenyl]ethanoic acid, ... (7 entities in total)
• Functional Keywords: sucnr1, gpr91, gpcr, g-protein coupled receptor, nanobody, antagonist, succinate, complex, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 60621.49

Authors

Haffke, M.,Jaakola, V.-P. (deposition date: 2019-05-08, release date: 2019-08-14, Last modification date: 2024-11-20)

Primary citation

Haffke, M.,Fehlmann, D.,Rummel, G.,Boivineau, J.,Duckely, M.,Gommermann, N.,Cotesta, S.,Sirockin, F.,Freuler, F.,Littlewood-Evans, A.,Kaupmann, K.,Jaakola, V.P.
Structural basis of species-selective antagonist binding to the succinate receptor.
Nature, 574:581-585, 2019

PubMed Abstract: The tricarboxylic acid cycle intermediate succinate is involved in metabolic processes and plays a crucial role in the homeostasis of mitochondrial reactive oxygen species. The receptor responsible for succinate signalling, SUCNR1 (also known as GPR91), is a member of the G-protein-coupled-receptor family and links succinate signalling to renin-induced hypertension, retinal angiogenesis and inflammation. Because SUCNR1 senses succinate as an immunological danger signal-which has relevance for diseases including ulcerative colitis, liver fibrosis, diabetes and rheumatoid arthritis-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.

PubMed: 31645725
DOI: 10.1038/s41586-019-1663-8

Experimental method

X-RAY DIFFRACTION (1.94 Å)