Ligand-Dependent Modulation of G Protein Conformation Alters Drug Efficacy

Sebastian George Barton Furness, Yi Lynn Liang, Cameron James Nowell, Michelle Louise Halls, Peter John Wookey, Emma Dal Maso, Asuka Inoue, Arthur Christopoulos, Denise Wootten, Patrick Michael Sexton

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

G protein-coupled receptor (GPCR) signaling, mediated by hetero-trimeric G proteins, can be differentially controlled by agonists. At a molecular level, this is thought to occur principally via stabilization of distinct receptor conformations by individual ligands. These distinct conformations control subsequent recruitment of transducer and effector proteins. Here, we report that ligand efficacy at the calcitonin GPCR (CTR) is also correlated with ligand-dependent alterations to G protein conformation. We observe ligand-dependent differences in the sensitivity of the G protein ternary complex to disruption by GTP, due to conformational differences in the receptor-bound G protein hetero-trimer. This results in divergent agonist-dependent receptor-residency times for the hetero-trimeric G protein and different accumulation rates for downstream second messengers. This study demonstrates that factors influencing efficacy extend beyond receptor conformation(s) and expands understanding of the molecular basis for how G proteins control/influence efficacy. This has important implications for the mechanisms that underlie ligand-mediated biased agonism. Video Abstract

Original languageEnglish
Pages (from-to)739-749.e11
JournalCell
Volume167
Issue number3
DOIs
Publication statusPublished - 2016 Oct 20

Keywords

  • BRET
  • CTR
  • FRET
  • G protein-coupled receptor
  • GPCR
  • TIRF
  • calcitonin
  • calcitonin receptor
  • efficacy
  • native PAGE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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