ArticleThe Journal of biological chemistry2010
Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 92 citations in OpenAlex.
- Article
- Cancer-Associated Mutations of the Adenosine AMolecules (Basel, Switzerland) · 2022Article
- Article
- Identification of V6.51L as a selectivity hotspot in stereoselective AScientific reports · 2021Article
- Allosteric communication regulates ligand-specific GPCR activity.The FEBS journal · 2021Review
- Structure-based identification of dual ligands at the AJournal of cheminformatics · 2021Article
- Activation Microswitches in Adenosine Receptor ABiochemistry · 2020Article
- Ligand-induced conformational changes in a SMALP-encapsulated GPCR.Biochimica et biophysica acta. Biomembranes · 2020Article
- An exploration strategy improves the diversity of de novo ligands using deep reinforcement learning: a case for the adenosine AJournal of cheminformatics · 2019Article
- Article
- Role of Extracellular Loops and Membrane Lipids for Ligand Recognition in the Neuronal Adenosine Receptor Type 2A: An Enhanced Sampling Simulation Study.Molecules (Basel, Switzerland) · 2018Article
- Article
- Role of extracellular cysteine residues in the adenosine A2A receptor.Purinergic signalling · 2016Article
- Molecular Determinants of CGS21680 Binding to the Human Adenosine A2A Receptor.Molecular pharmacology · 2015Article
- Conserved disulfide bond is not essential for the adenosine A2A receptor: Extracellular cysteines influence receptor distribution within the cell and ligand-binding recognition.Biochimica et biophysica acta · 2015Article
- Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.PloS one · 2014Article
- Discovery of 3,4-Dihydropyrimidin-2(1H)-ones As a Novel Class of Potent and Selective A2B Adenosine Receptor Antagonists.ACS medicinal chemistry letters · 2013Article
- Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor.Journal of the American Chemical Society · 2013Article
- Homology models of melatonin receptors: challenges and recent advances.International journal of molecular sciences · 2013Review
- The GPCR Network: a large-scale collaboration to determine human GPCR structure and function.Nature reviews. Drug discovery · 2013Review
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Authors and funding
6 authors at 2 institutions in 3 countries.
Funding
Abstract
The crystal structure of the human A(2A) adenosine receptor bound to the A(2A) receptor-specific antagonist, ZM241385, was recently determined at 2.6-A resolution. Surprisingly, the antagonist binds in an extended conformation, perpendicular to the plane of the membrane, and indicates a number of interactions unidentified before in ZM241385 recognition. To further understand the selectivity of ZM241385 for the human A(2A) adenosine receptor, we examined the effect of mutating amino acid residues within the binding cavity likely to have key interactions and that have not been previously examined. Mutation of Phe-168 to Ala abolishes both agonist and antagonist binding as well as receptor activity, whereas mutation of this residue to Trp or Tyr had only moderate effects. The Met-177 --> Ala mutation impeded antagonist but not agonist binding. Finally, the Leu-249 --> Ala mutant showed neither agonist nor antagonist binding affinity. From our results and previously published mutagenesis data, we conclude that conserved residues Phe-168(5.29), Glu-169(5.30), Asn-253(6.55), and Leu-249(6.51) play a central role in coordinating the bicyclic core present in both agonists and antagonists. By combining the analysis of the mutagenesis data with a comparison of the sequences of different adenosine receptor subtypes from different species, we predict that the interactions that determine subtype selectivity reside in the more divergent "upper" region of the binding cavity while the "lower" part of the binding cavity is conserved across adenosine receptor subtypes.
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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.