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

October 23, 2019

Haffke, M., Fehlmann, D., Rummel, G., et al.

Nature 2019, vol: 574 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 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 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.

View Publication

Topics: Prometheus, nanoDSF, Membrane Proteins, Publications

Previous Article
How Amgen looks at stability characterization to boost the success of biologics candidates
How Amgen looks at stability characterization to boost the success of biologics candidates

Biologic drugs have been incredibly successful in terms of both medical achievement and profitability. Many...

Up next
High-throughput stability screening for detergent-solubilized membrane proteins
High-throughput stability screening for detergent-solubilized membrane proteins

Have a question about Prometheus?

Contact Specialist
×

Sign up to receive
the latest NanoTemper news, product updates, event announcements and more

First Name
Last Name
Company Name
Country
State
Province
State
Region
State
Canton
Agree to Subscribe & Privacy Policy*
*I have fully read, understood and agree to the Privacy Policy. I accept the storing and processing of my personal data by NanoTemper as described in the Privacy Policy.

By completing this form, you provide us consent to contact you with educational content, news and information about our products, services and events. You may unsubscribe at any time.
Thank you!
Error - something went wrong!