ArticleMolecular pharmacology2015
Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor.
Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Antihypertensive Efficacy and Safety of Angiotensin Receptor Blockers (ARBs) with and without Inverse Agonism: A Systematic Review and Network Meta-analysis.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2026Pooled it
- Angiotensin II Type 1 Receptor Expression and Anti-AT1R Antibodies in Heart Transplantation: A Systematic Review of Distinct but Related Non-HLA Immune Pathways.Journal of clinical medicine · 2026Review
- Latest Knowledge on the Role of Vitamin D in Hypertension.International journal of molecular sciences · 2023Review
- Losartan as an ACE inhibitor: a description of the mechanism of action through quantum biochemistry.RSC advances · 2022Article
- Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34.British journal of pharmacology · 2022Review
- GPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation.Nature communications · 2022Article
- Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain.Molecules (Basel, Switzerland) · 2021Review
- The endocytosis of oxidized LDL via the activation of the angiotensin II type 1 receptor.iScience · 2021Article
- Insights into the actions of angiotensin-1 receptor (AT1R) inverse agonists: Perspectives and implications in COVID-19 treatment.EXCLI journal · 2021Review
- Prevalence of Angiotensin II Type 1 Receptor Antibodies in Persons With Hypertension and Relation to Blood Pressure and Medication.American journal of hypertension · 2020Article
- Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy.International journal of molecular sciences · 2019Review
- Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of ATJournal of chemical information and modeling · 2019Article
- Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog.Nature structural & molecular biology · 2018Article
- The non-biphenyl-tetrazole angiotensin ATBritish journal of pharmacology · 2018Article
- Divergent Spatiotemporal Interaction of Angiotensin Receptor Blocking Drugs with Angiotensin Type 1 Receptor.Journal of chemical information and modeling · 2018Article
- Article
- Current topics in angiotensin II type 1 receptor research: Focus on inverse agonism, receptor dimerization and biased agonism.Pharmacological research · 2017Review
- Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.Oncotarget · 2017Article
- Role of agonistic autoantibodies against type-1 angiotensin II receptor in the pathogenesis of retinopathy in preeclampsia.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 3 countries.
Funding
Abstract
Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109(TM3), Phe182(ECL2), Gln257(TM6), Tyr292(TM7), and Asn295(TM7)) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108(TM3), Ser109(TM3), Ala163(TM4), Phe182(ECL2), Lys199(TM5), Tyr292(TM7), and Asn295(TM7)), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.