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

Denise Laura Wootten, John Watson Simms, Laurence J Miller, Arthur Christopoulos, Patrick Sexton

Research output: Contribution to journalArticleResearchpeer-review

136 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)5211 - 5216
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
Publication statusPublished - 2013

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