ArticleThe Journal of biological chemistry2015
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.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 30 citations in OpenAlex.
- Development of a Non-Peptide Angiotensin II Type 1 Receptor Ligand by Structural Modification of Olmesartan as a Biased Agonist.Biomedicines · 2023Article
- Agonist concentration-dependent changes in FPR1 conformation lead to biased signaling for selective activation of phagocyte functions.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- ATRAP, a receptor-interacting modulator of kidney physiology, as a novel player in blood pressure and beyond.Hypertension research : official journal of the Japanese Society of Hypertension · 2022Review
- Biochemical and physiological insights into TRH receptor-mediated signaling.Frontiers in cell and developmental biology · 2022Review
- β-arrestin-1 and β-arrestin-2 Restrain MRGPRX2-Triggered Degranulation and ERK1/2 Activation in Human Skin Mast Cells.Frontiers in allergy · 2022Article
- Structural insights into ligand recognition and activation of angiotensin receptors.Trends in pharmacological sciences · 2021Review
- Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes.International journal of molecular sciences · 2021Review
- Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.Science (New York, N.Y.) · 2020Article
- Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR.Science (New York, N.Y.) · 2020Article
- S-nitrosoglutathione inhibits cerebrovascular angiotensin II-dependent and -independent ATBritish journal of pharmacology · 2019Article
- Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of ATJournal of chemical information and modeling · 2019Article
- The Role of β-Arrestin Proteins in Organization of Signaling and Regulation of the AT1 Angiotensin Receptor.Frontiers in endocrinology · 2019Review
- Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog.Nature structural & molecular biology · 2018Article
- Ligand-specific conformational transitions and intracellular transport are required for atypical chemokine receptor 3-mediated chemokine scavenging.The Journal of biological chemistry · 2018Article
- The orientation and stability of the GPCR-Arrestin complex in a lipid bilayer.Scientific reports · 2017Article
- Biased agonism and allosteric modulation of G protein-coupled receptor 183 - a 7TM receptor also known as Epstein-Barr virus-induced gene 2.British journal of pharmacology · 2017Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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