ArticleBritish journal of pharmacology2013
Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor.
Article in British journal of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Activity-restoring mutations in the histamine HProtein science : a publication of the Protein Society · 2026Article
- MDPath: Unraveling Allosteric Communication Paths of Drug Targets through Molecular Dynamics Simulations.Journal of chemical information and modeling · 2025Article
- Quantitative approaches for studying G protein-coupled receptor signalling and pharmacology.Journal of cell science · 2025Review
- Recovery of the histamine HScientific reports · 2023Article
- Sub-millisecond conformational dynamics of the ACommunications biology · 2023Article
- A methodology for creating mutants of G-protein coupled receptors stabilized in active state by combining statistical thermodynamics and evolutionary molecular engineering.Protein science : a publication of the Protein Society · 2022Article
- Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel.Nature communications · 2021Article
- Characterization of binding kinetics of ABiophysical journal · 2021Article
- Crystal Structure and Subsequent Ligand Design of a Nonriboside Partial Agonist Bound to the Adenosine AJournal of medicinal chemistry · 2021Article
- The Specificity of Downstream Signaling for ABiomedicines · 2020Article
- Functional Expression of Adenosine AInternational journal of molecular sciences · 2020Article
- Ligand-induced conformational changes in a SMALP-encapsulated GPCR.Biochimica et biophysica acta. Biomembranes · 2020Article
- Bridging non-overlapping reads illuminates high-order epistasis between distal protein sites in a GPCR.Nature communications · 2020Article
- Experimental and computational analysis of biased agonism on full-length and a C-terminally truncated adenosine AComputational and structural biotechnology journal · 2020Article
- Article
- Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).The Journal of biological chemistry · 2015Article
- Pharmacological properties of acid N-thiazolylamide FFA2 agonists.Pharmacology research & perspectives · 2015Article
- Investigating G protein signalling bias at the glucagon-like peptide-1 receptor in yeast.British journal of pharmacology · 2014Article
- Arginine 199 and leucine 208 have key roles in the control of adenosine A2A receptor signalling function.PloS one · 2014Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThermostabilization by mutagenesis is one method which has facilitated the determination of high-resolution structures of the adenosine A2A receptor (A(2A)R). Sets of mutations were identified, which both thermostabilized the receptor and resulted in preferential agonist (Rag23 mutant) or antagonist (Rant5 and Rant21) binding forms as assessed by radioligand binding analysis. While the ligand-binding profiles of these mutants are known, the effects these mutations have on receptor activation and downstream signalling are less well characterized. EXPERIMENTAL APPROACH: Here we have investigated the effects of the thermostabilizing mutations on receptor activation using a yeast cell growth assay. The assay employs an engineered Saccharomyces cerevisiae, MMY24, which couples receptor activation to cell growth. KEY
resultsAnalysis of the receptor activation profile revealed that the wild-type (WT) A(2A)R had considerable constitutive activity. In contrast, the Rag23, Rant5 and Rant21 thermostabilized mutants all exhibited no constitutive activity. While the preferentially antagonist-binding mutants Rant5 and Rant21 showed a complete lack of agonist-induced activity, the Rag23 mutant showed high levels of agonist-induced receptor activity. Further analysis using a mutant intermediate between Rag23 and WT indicated that the loss of constitutive activity observed in the agonist responsive mutants was not due to reduced G-protein coupling. CONCLUSIONS AND IMPLICATIONS: The loss of constitutive activity may be an important feature of these thermostabilized GPCRs. In addition, the constitutively active and agonist-induced active conformations of the A(2A)R are distinct.
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