Structural basis for GPCR signaling by small polar versus large lipid metabolites-discovery of non-metabolite ligands.

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ID: 83281
2020
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Abstract
Key metabolites act through specific G protein-coupled receptors (GPCRs) as extracellular signals of fuel availability and metabolic stress. Here, we focus on the succinate receptor SUCNR1/GPR91 and the long chain fatty acid receptor FFAR1/GPR40, for which 3D structural information is available. Like other small polar acidic metabolites, succinate is excreted from the cell by transporter proteins to bind to an extracellular, solvent-exposed pocket in SUCNR1. Non-metabolite pharmacological tool compounds are currently being designed based on the structure of the SUCNR1 binding pocket. In FFAR1, differently signaling lipid mimetics bind in two distinct membrane-exposed sites corresponding to each of the lipid bilayer leaflets. Conceivably endogenous lipid ligands gain access to these sites by way of the membrane and probably occupy both sites under physiological circumstances. Design of polar agonists for a dynamic, solvent-exposed pocket in FFAR1 underlines the possibility of structure-based approaches for development of novel tool compounds even in lipid sensing metabolite GPCRs.
Reference Key
luckmann2020structuralcurrent Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Lückmann, Michael;Trauelsen, Mette;Frimurer, Thomas M;Schwartz, Thue W;
Journal current opinion in cell biology
Year 2020
DOI
S0955-0674(19)30115-2
URL
Keywords
gpcr long chain fatty acid receptor metabolite receptors metabolite signaling structure-based drug discovery succinate receptor

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