ArticleThe Journal of biological chemistry2013
Long range effect of mutations on specific conformational changes in the extracellular loop 2 of angiotensin II type 1 receptor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- Bioinformatics Analysis of Mutations Sheds Light on the Evolution of Dengue NS1 Protein With Implications in the Identification of Potential Functional and Druggable Sites.Molecular biology and evolution · 2023Article
- Activation and Speciation Mechanisms in Class A GPCRs.Journal of molecular biology · 2022Article
- Article
- Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation.International journal of molecular sciences · 2022Article
- Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting.Frontiers in endocrinology · 2022Review
- Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of ATJournal of chemical information and modeling · 2019Article
- The non-biphenyl-tetrazole angiotensin ATBritish journal of pharmacology · 2018Article
- Current topics in angiotensin II type 1 receptor research: Focus on inverse agonism, receptor dimerization and biased agonism.Pharmacological research · 2017Review
- Luminal ANG II is internalized as a complex with ATAmerican journal of physiology. Renal physiology · 2017Article
- ATBMC cardiovascular disorders · 2017Article
- Differential Contribution of Transmembrane Domains IV, V, VI, and VII to Human Angiotensin II Type 1 Receptor Homomer Formation.The Journal of biological chemistry · 2017Article
- New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model.Biochemical pharmacology · 2016Review
- The importance of non-HLA antibodies in transplantation.Nature reviews. Nephrology · 2016Review
- Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor.The Journal of biological chemistry · 2015Article
- International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected].Pharmacological reviews · 2015Review
- Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor.Molecular pharmacology · 2015Article
- Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.ACS chemical biology · 2014Article
- Allosteric modulation of a cannabinoid G protein-coupled receptor: binding site elucidation and relationship to G protein signaling.The Journal of biological chemistry · 2014Article
- Identification of the GPR55 antagonist binding site using a novel set of high-potency GPR55 selective ligands.Biochemistry · 2013Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The topology of the second extracellular loop (ECL2) and its interaction with ligands is unique in each G protein-coupled receptor. When the orthosteric ligand pocket located in the transmembrane (TM) domain is occupied, ligand-specific conformational changes occur in the ECL2. In more than 90% of G protein-coupled receptors, ECL2 is tethered to the third TM helix via a disulfide bond. Therefore, understanding the extent to which the TM domain and ECL2 conformations are coupled is useful. To investigate this, we examined conformational changes in ECL2 of the angiotensin II type 1 receptor (AT1R) by introducing mutations in distant sites that alter the activation state equilibrium of the AT1R. Differential accessibility of reporter cysteines introduced at four conformation-sensitive sites in ECL2 of these mutants was measured. Binding of the agonist angiotensin II (AngII) and inverse agonist losartan in wild-type AT1R changed the accessibility of reporter cysteines, and the pattern was consistent with ligand-specific "lid" conformations of ECL2. Without agonist stimulation, the ECL2 in the gain of function mutant N111G assumed a lid conformation similar to AngII-bound wild-type AT1R. In the presence of inverse agonists, the conformation of ECL2 in the N111G mutant was similar to the inactive state of wild-type AT1R. In contrast, AngII did not induce a lid conformation in ECL2 in the loss of function D281A mutant, which is consistent with the reduced AngII binding affinity in this mutant. However, a lid conformation was induced by [Sar(1),Gln(2),Ile(8)] AngII, a specific analog that binds to the D281A mutant with better affinity than AngII. These results provide evidence for the emerging paradigm of domain coupling facilitated by long range interactions at distant sites on the same receptor.
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