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Updated: Sep 15, 2025
09:12
G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay
Published on: September 10, 2016
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Protein Frustration Reveals Active Sites in Co-Evolved GPCR:G Protein Complexes and in Engineered Targeted Degrader
Wenyuan Wei1,2, Roland Del Mundo1,2, Tianyi Yang1
1Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, 1218 S 5th Ave, Monrovia, CA 91016.
Biorxiv : the Preprint Server for Biology
|July 16, 2025
Summary
Protein frustration, a suboptimal energy state, is concentrated at interfaces in G protein-coupled receptors (GPCRs) and their interacting partners. This finding aids in evaluating native and engineered protein complexes.
Area of Science:
- Structural biology
- Biophysics
- Molecular pharmacology
Background:
- Proteins naturally fold into optimal energy states.
- Certain functionally critical residues can exist in suboptimal, or
- frustrated
- states.
- Protein frustration is a measure of energetic instability at specific residue positions.
Purpose of the Study:
- To investigate the distribution and significance of protein frustration at interfaces within G protein-coupled receptor (GPCR) complexes.
- To compare frustration levels in native protein-protein interactions versus engineered complexes.
Main Methods:
- Analysis of over 1200 three-dimensional structures of GPCRs and associated proteins.
- Computational assessment of residue energy states to identify "frustrated" sites.
- Mapping frustrated residues to known ligand, G protein, and effector binding interfaces.
Main Results:
- Residues at GPCR-ligand and GPCR-G protein interfaces exhibit higher frustration density than other receptor regions.
- The Gα subunit surface shows frustrated residue clusters at effector binding sites (e.g., Gβγ, Adenyl cyclase).
- Engineered protein complexes (e.g., molecular degraders) display significantly higher frustration at their interfaces compared to native complexes.
Conclusions:
- Protein frustration is a key indicator for assessing the stability and characteristics of native protein-protein interfaces.
- The concept of protein frustration can guide the design and optimization of engineered protein complexes for therapeutic and research applications.
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