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Nature. 2019 Oct;574(7779):581-585. doi: 10.1038/s41586-019-1663-8. Epub 2019 Oct 23.

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

Author information

1
Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. matthias.haffke@novartis.com.
2
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. matthias.haffke@novartis.com.
3
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
4
Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
5
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
6
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. klemens.kaupmann@novartis.com.
7
Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. veli-pekka.jaakola@confotherapeutics.com.
8
Confo Therapeutics, Zwijnaarde, Belgium. veli-pekka.jaakola@confotherapeutics.com.

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.

PMID:
31645725
DOI:
10.1038/s41586-019-1663-8
[Indexed for MEDLINE]

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