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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
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Structure and Function of Peptide-Binding G Protein-Coupled Receptors
Fan Wu1, Gaojie Song1, Chris de Graaf2
1iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
Journal of Molecular Biology
|July 15, 2017
Summary
G protein-coupled receptors (GPCRs) are key drug targets. This review analyzes peptide-binding GPCR structures, revealing small molecules dominate drug development, distinct from peptide ligands.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors, crucial for human drug development.
- 118 of 826 human GPCRs bind peptide/protein ligands, with 30 targeted by approved drugs, including the glucagon-like peptide 1 receptor.
Purpose of the Study:
- To analyze the 21 determined 3D structures of peptide-binding GPCRs.
- To compare structures with endogenous peptides and modulating drug molecules.
- To understand ligand-receptor interactions and signaling.
Main Methods:
- Analysis of 21 experimentally determined three-dimensional structures of peptide-binding GPCRs.
- Integration of data from orthogonal biophysical techniques like nuclear magnetic resonance and electron microscopy.
Main Results:
- Half of marketed drugs and most drugs in clinical trials for peptide GPCRs are small molecules.
- These small molecules exhibit diverse binding modes, differing from large peptide ligands.
- Structural insights reveal distinct interaction patterns between GPCRs and their ligands.
Conclusions:
- Understanding GPCR pharmacology requires studying ligand interactions at the molecular level.
- Multiple biophysical techniques are essential for comprehensive analysis of GPCR signal transduction.
- Small molecules represent a significant and evolving class of therapeutics for peptide GPCRs.
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