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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding
Bill X Huang1, Xin Hu2, Heung-Sun Kwon1
1Laboratory of Molecular Signaling, National Institute on Alcohol Abuse and Alcoholism, NIH, 5625 Fishers Lane, Rockville, MD, 20852, USA.
Communications Biology
|March 8, 2020
Summary
Scientists uncovered how synaptamide activates the GPR110 receptor by binding to its GAIN domain. This discovery explains adhesion G protein-coupled receptor (aGPCR) activation and offers therapeutic targets.
Area of Science:
- Molecular biology
- Biochemistry
- Structural biology
Background:
- Adhesion G protein-coupled receptors (aGPCRs) possess large extracellular regions with a conserved GPCR-autoproteolysis-inducing (GAIN) domain.
- The precise molecular mechanisms underlying aGPCR physiological activation remain largely unknown, despite their involvement in various diseases.
Purpose of the Study:
- To elucidate the molecular basis of synaptamide-mediated activation of the GPR110 receptor (ADGRF1) in living cells.
- To identify the specific binding site and conformational changes induced by synaptamide within the GPR110 GAIN domain.
Main Methods:
- In-cell chemical cross-linking coupled with mass spectrometry (XC-MS).
- Computational modeling and molecular dynamics simulations.
- Mutagenesis-assisted functional assays in living cells.
Main Results:
- Synaptamide was identified as the first and only known endogenous small-molecule ligand for an aGPCR, binding to GPR110.
- Synaptamide specifically binds at the interface of GPR110 GAIN subdomains, involving key residues Q511, N512, and Y513.
- This binding induces a conformational change near transmembrane helix 6 (TM6), initiating downstream signaling.
Conclusions:
- The study reveals a novel ligand-induced activation mechanism for aGPCRs, specifically targeting the GAIN domain.
- This mechanism provides a framework for understanding aGPCR physiological roles.
- The findings offer potential therapeutic strategies targeting the GAIN domain for diseases involving aGPCRs.
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