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

Haffke, Matthias and Fehlmann, Dominique and Rummel, Gabriele and Boivineau, Jacques and Duckely, Myriam and Gommermann, Nina and Cotesta, Simona and Sirockin, Finton and Freuler, Felix and Littlewood-Evans, Amanda and Kaupmann, Klemens and Jaakola, Veli-Pekka (2019) Structural basis of species-selective antagonist binding to the succinate receptor. Nature, 574. pp. 581-585.

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 speciesselective
antagonist binding and enabled the determination of the high-resolution
crystal structure of a humanized rat SUCNR1 in complex with a high-affinity, humanselective
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.

Item Type: Article
Date Deposited: 09 Nov 2019 00:45
Last Modified: 09 Nov 2019 00:45
URI: https://oak.novartis.com/id/eprint/41247

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