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
AN - SCOPUS:85049200485
VL - 293
SP - 9370
EP - 9387
JO - The Journal of Biological Chemistry
JF - The Journal of Biological Chemistry
SN - 1083-351X
IS - 24
ER -