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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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Conserved class B GPCR activation by a biased intracellular agonist
Li-Hua Zhao1,2, Qian He3,4, Qingning Yuan3
1State Key Laboratory of Drug Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaolihuawendy@simm.ac.cn.
Nature
|July 31, 2023
Summary
Researchers discovered a new binding site for small-molecule drugs targeting the parathyroid hormone 1 receptor (PTH1R). This finding could lead to orally available drugs for class B G-protein-coupled receptors (GPCRs).
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Class B G-protein-coupled receptors (GPCRs), such as GLP1R and PTH1R, are crucial drug targets.
- While peptide drugs exist, orally available small-molecule drugs for these receptors are still under development.
Purpose of the Study:
- To determine the high-resolution structure of human PTH1R bound to a G protein and a small-molecule agonist.
- To elucidate the binding mode of the small-molecule agonist PCO371 and its implications for drug design.
Main Methods:
- High-resolution structural analysis of human PTH1R complexed with Gs and PCO371.
- Functional assays to assess PCO371's agonistic activity and signaling bias.
- Site-directed mutagenesis studies on PTH2R and GLP1R to investigate PCO371 binding conservation.
Main Results:
- A novel binding site for the small-molecule agonist PCO371 was identified at the cytoplasmic interface of PTH1R with Gs.
- This binding site differs significantly from previously known GPCR ligand-binding sites.
- PCO371 acts as a G-protein-biased agonist, selectively activating Gs signaling over arrestin signaling.
- Conserved residues in the PCO371-binding pocket suggest potential for targeting other class B GPCRs.
Conclusions:
- The discovery of a distinct PCO371-binding site on PTH1R opens new avenues for designing orally available small-molecule agonists.
- This finding facilitates the development of biased agonists that selectively modulate G-protein signaling, potentially leading to improved therapeutics.
- The conserved nature of the binding pocket offers a promising strategy for targeting a broader range of class B GPCRs.
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