title: Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations.
abstract: 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.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia. denise.wootten@monash.edu
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.forename: John
authors.initials: J
authors.lastname: Simms
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008024:Ligands; D053772:Oxyntomodulin / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014688:Venoms / Q000494:pharmacology*
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D008024:Ligands; D053772:Oxyntomodulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide