6ibb

Publication Abstract from PubMed

The tricarboxylic acid cycle intermediate succinate is involved in metabolic processes and plays a crucial role in the homeostasis of mitochondrial reactive oxygen species(1). The receptor responsible for succinate signalling, SUCNR1 (also known as GPR91), is a member of the G-protein-coupled-receptor family(2) and links succinate signalling to renin-induced hypertension, retinal angiogenesis and inflammation(3-5). Because SUCNR1 senses succinate as an immunological danger signal(6)-which has relevance for diseases including ulcerative colitis, liver fibrosis(7), diabetes and rheumatoid arthritis(3,8)-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.

Structural basis of species-selective antagonist binding to the succinate receptor.,Haffke M, Fehlmann D, Rummel G, Boivineau J, Duckely M, Gommermann N, Cotesta S, Sirockin F, Freuler F, Littlewood-Evans A, Kaupmann K, Jaakola VP Nature. 2019 Oct;574(7779):581-585. doi: 10.1038/s41586-019-1663-8. Epub 2019 Oct, 23. PMID:31645725^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.