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

Matthias Haffke (), Dominique Fehlmann, Gabriele Rummel, Jacques Boivineau, Myriam Duckely, Nina Gommermann, Simona Cotesta, Finton Sirockin, Felix Freuler, Amanda Littlewood-Evans, Klemens Kaupmann () and Veli-Pekka Jaakola ()
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Matthias Haffke: Novartis Pharma AG
Dominique Fehlmann: Novartis Pharma AG
Gabriele Rummel: Novartis Pharma AG
Jacques Boivineau: Novartis Pharma AG
Myriam Duckely: Novartis Pharma AG
Nina Gommermann: Novartis Pharma AG
Simona Cotesta: Novartis Pharma AG
Finton Sirockin: Novartis Pharma AG
Felix Freuler: Novartis Pharma AG
Amanda Littlewood-Evans: Novartis Pharma AG
Klemens Kaupmann: Novartis Pharma AG
Veli-Pekka Jaakola: Novartis Pharma AG

Nature, 2019, vol. 574, issue 7779, 581-585

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1663-8

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