Ligand-dependent modulation of G protein conformation alters drug efficacy

Research output: Contribution to journalArticleResearchpeer-review

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. Ligand binding to a G protein-coupled receptor not only affects the receptor conformation, but also modulates the bound G protein to shape downstream signaling.

Original languageEnglish
Pages (from-to)739-749
Number of pages11
JournalCell
Volume167
Issue number3
DOIs
Publication statusPublished - 20 Oct 2016

Keywords

  • BRET
  • Calcitonin
  • Calcitonin receptor
  • CTR
  • Efficacy
  • FRET
  • G protein-coupled receptor
  • GPCR
  • Native PAGE
  • TIRF

Cite this

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title = "Ligand-dependent modulation of G protein conformation alters drug efficacy",
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. Ligand binding to a G protein-coupled receptor not only affects the receptor conformation, but also modulates the bound G protein to shape downstream signaling.",
keywords = "BRET, Calcitonin, Calcitonin receptor, CTR, Efficacy, FRET, G protein-coupled receptor, GPCR, Native PAGE, TIRF",
author = "Furness, {Sebastian George Barton} and Yi-Lynn Liang and Nowell, {Cameron James} and Halls, {Michelle Louise} and Wookey, {Peter John} and {Dal Maso}, Emma and Asuka Inoue and Arthur Christopoulos and Denise Wootten and Sexton, {Patrick Michael}",
year = "2016",
month = "10",
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doi = "10.1016/j.cell.2016.09.021",
language = "English",
volume = "167",
pages = "739--749",
journal = "Cell",
issn = "0092-8674",
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Ligand-dependent modulation of G protein conformation alters drug efficacy. / Furness, Sebastian George Barton; Liang, Yi-Lynn; Nowell, Cameron James; Halls, Michelle Louise; Wookey, Peter John; Dal Maso, Emma; Inoue, Asuka; Christopoulos, Arthur; Wootten, Denise; Sexton, Patrick Michael.

In: Cell, Vol. 167, No. 3, 20.10.2016, p. 739-749.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Ligand-dependent modulation of G protein conformation alters drug efficacy

AU - Furness, Sebastian George Barton

AU - Liang, Yi-Lynn

AU - Nowell, Cameron James

AU - Halls, Michelle Louise

AU - Wookey, Peter John

AU - Dal Maso, Emma

AU - Inoue, Asuka

AU - Christopoulos, Arthur

AU - Wootten, Denise

AU - Sexton, Patrick Michael

PY - 2016/10/20

Y1 - 2016/10/20

N2 - 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. Ligand binding to a G protein-coupled receptor not only affects the receptor conformation, but also modulates the bound G protein to shape downstream signaling.

AB - 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. Ligand binding to a G protein-coupled receptor not only affects the receptor conformation, but also modulates the bound G protein to shape downstream signaling.

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KW - TIRF

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