Protein Frustration Reveals Orthosteric and Allosteric Active Sites in GPCR:G Protein Complexes
TL;DR
This study leverage over 1200 three-dimensional structures of G protein-coupled receptors (GPCRs) to demonstrate that residues at the interface between GPCR and its ligand or G protein contain a higher density of frustrated residues compared to other structural regions in the receptor.
Abstract
The folded structure of a protein is understood to be an optimal energy state. However, previous studies have shown that certain amino acid residue positions that play a critical role in protein function are often in a suboptimal energy state or “frustrated”. Here, we leverage over 1200 three-dimensional structures of G protein-coupled receptors (GPCRs) to demonstrate that residues at the interface between GPCR and its ligand or G protein contain a higher density of frustrated residues compared to other structural regions in the receptor. Likewise, the Gα subunit of the trimeric G proteins shows multiple clusters of highly frustrated residues on its surface that overlap with their effector protein (Gbγ, RGS, Adenylyl cyclase, Ric8) binding interfaces. Our study highlights the use of protein frustration as one of the multiple structural properties to identify protein–protein interfaces and for prospective prediction of potential ligand binding sites.