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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 13; pp. 5211 - 5216
• Main Authors: Wootten, Denise, Simms, John, Miller, Laurence J., Christopoulos, Arthur, Sexton, Patrick M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26-03-2013; National Acad Sciences
• Subjects: Agonists; Animals; Biological Sciences; Cell Membrane - genetics; Cell Membrane - metabolism; Cell membranes; CHO Cells; Cricetinae; Cricetulus; Drug interactions; Gene expression; Glucagon-Like Peptide-1 Receptor; Humans; Hydrogen; Hydrogen bonds; Hypoglycemic Agents - pharmacology; Ligands; Membrane proteins; Membranes; Mutagenesis; Oxyntomodulin - pharmacology; Peptides; Peptides - pharmacology; Protein folding; Receptors; Receptors, Glucagon - agonists; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Statistical significance; Venoms - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1221585110

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