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 language | English |
|---|---|
| Pages (from-to) | 739-749 |
| Number of pages | 11 |
| Journal | Cell |
| Volume | 167 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 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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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 journal › Article › Research › peer-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.
KW - BRET
KW - Calcitonin
KW - Calcitonin receptor
KW - CTR
KW - Efficacy
KW - FRET
KW - G protein-coupled receptor
KW - GPCR
KW - Native PAGE
KW - TIRF
UR - http://www.scopus.com/inward/record.url?scp=84993927615&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2016.09.021
DO - 10.1016/j.cell.2016.09.021
M3 - Article
VL - 167
SP - 739
EP - 749
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -