Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations

• DOI: 10.1073/pnas.1221585110
• Publication Date: 2013-03-12T01:09:22Z
• Authors: Denise Wootten; John Simms; Laurence J. Miller; Arthur Christopoulos; Patrick M. Sexton
• Keywords: Functional selectivity

Recently, the concept of ligand-directed signaling—the ability different ligands an individual receptor to promote distinct patterns cellular response—has gained much traction in field drug discovery, with potential sculpt biological response favor therapeutically beneficial signaling pathways over those leading harmful effects. However, there is limited understanding mechanistic basis underlying biased signaling. The glucagon-like peptide-1 a major target for treatment type-2 diabetes and subject Here, we demonstrate importance polar transmembrane residues conserved within family B G protein-coupled receptors, not only protein folding expression, but also controlling activation transition, ligand-biased, pathway-biased Distinct clusters were important signal preference, globally changing profile peptide ligands, including endogenous peptide-1, oxyntomodulin, clinically used mimetic exendin-4.