Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor

Abstract

Background: GPCRs adopt multiple active states, resulting in pathway-biased signaling. Results: A novel method for quantifying stimulus bias was applied to mutational analysis of the M2 muscarinic GPCR. Conclusion: We established that aromatic residues in an allosteric site regulate the activation state of the receptor. Significance: The combination of mutagenesis with statistical quantification of stimulus bias results in enriched structurefunction relationships at GPCRs. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.