Abstract
G protein? coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/Gs protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal?regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide?receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism.
| Original language | English |
|---|---|
| Pages (from-to) | 9370-9387 |
| Number of pages | 18 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - 1 Jan 2018 |
Cite this
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Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism. / Lei, Saifei; Clydesdale, Lachlan ; Dai, Antao; Cai, Xiaoqing ; Yang, Feng; Yang, Dehua; Liang, Yi-Lynn; Koole, Cassandra ; Zhao, Peishen; Coudrat, Thomas; Christopoulos, Arthur; Wang, Ming-Wei; Wootten, Denise ; Sexton, Patrick M.
In: Journal of Biological Chemistry, Vol. 293, No. 24, 01.01.2018, p. 9370-9387.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism
AU - Lei, Saifei
AU - Clydesdale, Lachlan
AU - Dai, Antao
AU - Cai, Xiaoqing
AU - Yang, Feng
AU - Yang, Dehua
AU - Liang, Yi-Lynn
AU - Koole, Cassandra
AU - Zhao, Peishen
AU - Coudrat, Thomas
AU - Christopoulos, Arthur
AU - Wang, Ming-Wei
AU - Wootten, Denise
AU - Sexton, Patrick M
PY - 2018/1/1
Y1 - 2018/1/1
N2 - G protein? coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/Gs protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal?regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide?receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism.
AB - G protein? coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/Gs protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal?regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide?receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism.
UR - http://www.scopus.com/inward/record.url?scp=85049200485&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.003278
DO - 10.1074/jbc.RA118.003278
M3 - Article
VL - 293
SP - 9370
EP - 9387
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 1083-351X
IS - 24
ER -