| Autor: |
Haffke M; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. matthias.haffke@novartis.com.; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. matthias.haffke@novartis.com., Fehlmann D; Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Rummel G; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Boivineau J; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Duckely M; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Gommermann N; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Cotesta S; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Sirockin F; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Freuler F; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Littlewood-Evans A; Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland., Kaupmann K; Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. klemens.kaupmann@novartis.com., Jaakola VP; Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. veli-pekka.jaakola@confotherapeutics.com.; Confo Therapeutics, Zwijnaarde, Belgium. veli-pekka.jaakola@confotherapeutics.com. |
| Abstrakt: |
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. |
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