2. Academic Validation
  3. Structural basis of species-selective antagonist binding to the succinate receptor

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

  • Nature. 2019 Oct;574(7779):581-585. doi: 10.1038/s41586-019-1663-8.
Matthias Haffke 1 2,  Dominique Fehlmann 3,  Gabriele Rummel 4,  Jacques Boivineau 4,  Myriam Duckely 4,  Nina Gommermann 5,  Simona Cotesta 5,  Finton Sirockin 5,  Felix Freuler 4,  Amanda Littlewood-Evans 3,  Klemens Kaupmann 6,  Veli-Pekka Jaakola 7 8
Affiliations

Affiliations

  • 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.
PMID: 31645725 DOI: 10.1038/s41586-019-1663-8
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.

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