Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations.
Biased signaling represents the ability of G protein-coupled receptors to engage distinct pathways with various efficacies depending on the ligand used or on mutations in the receptor. The angiotensin-II type 1 (AT1) receptor, a prototypical class A G protein-coupled receptor, can activate various effectors upon stimulation with the endogenous ligand angiotensin-II (AngII), including the Gq/11 protein and β-arrestins. It is believed that the activation of those two pathways can be associated with distinct conformations of the AT1 receptor. To verify this hypothesis, microseconds of molecular dynamics simulations were computed to explore the conformational landscape sampled by the WT-AT1 receptor, the N111G-AT1 receptor (constitutively active and biased for the Gq/11 pathway), and the D74N-AT1 receptor (biased for the β-arrestin1 and -2 pathways) in their apo-forms and in complex with AngII. The molecular dynamics simulations of the AngII-WT-AT1, N111G-AT1, and AngII-N111G-AT1 receptors revealed specific structural rearrangements compared with the initial and ground state of the receptor. Simulations of the D74N-AT1 receptor revealed that the mutation stabilizes the receptor in the initial ground state. The presence of AngII further stabilized the ground state of the D74N-AT1 receptor. The biased agonist [Sar(1),Ile(8)]AngII also showed a preference for the ground state of the WT-AT1 receptor compared with AngII. These results suggest that activation of the Gq/11 pathway is associated with a specific conformational transition stabilized by the agonist, whereas the activation of the β-arrestin pathway is linked to the stabilization of the ground state of the receptor.
Departments of Pharmacology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4; PROTEO (Quebec Network on Protein Structure, Function, and Engineering), Université Laval, Québec, Québec G1V 0A6, Canada.
Jérôme
J
Cabana
Departments of Pharmacology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4.
Brian
B
Holleran
Departments of Pharmacology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4.
Richard
R
Leduc
Departments of Pharmacology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4.
Emanuel
E
Escher
Departments of Pharmacology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4.
Gaétan
G
Guillemette
PROTEO (Quebec Network on Protein Structure, Function, and Engineering), Université Laval, Québec, Québec G1V 0A6, Canada; Biochemistry, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4. Electronic address: Pierre.Lavigne@USherbrooke.ca.
Pierre
P
Lavigne
D019943:Amino Acid Substitution; D019390:Arrestins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins
D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D000071557:beta-Arrestins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
AT1 receptor; AT1R; G protein-coupled receptor (GPCR); activation mechanism; angiotensin II; biased signaling; functional selectivity; molecular dynamics; protein conformation; receptor structure-function