ArticleBiophysical journal2012
Agonist dynamics and conformational selection during microsecond simulations of the A(2A) adenosine receptor.
Article in Biophysical journal, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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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
18 citing papers in PubMed.
- Mechanistic basis of GPCR activation explored by ensemble refinement of crystallographic structures.Protein science : a publication of the Protein Society · 2022Article
- Interacting binding insights and conformational consequences of the differential activity of cannabidiol with two endocannabinoid-activated G-protein-coupled receptors.Frontiers in pharmacology · 2022Article
- Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions.PLoS computational biology · 2020Article
- Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy.International journal of molecular sciences · 2019Review
- 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
- Identification of Two New Cholesterol Interaction Sites on the ABiophysical journal · 2017Article
- Structure-Activity Relationships of the Sustained Effects of Adenosine A2A Receptor Agonists Driven by Slow Dissociation Kinetics.Molecular pharmacology · 2017Article
- Ultraslow Water-Mediated Transmembrane Interactions Regulate the Activation of A2A Adenosine Receptor.Biophysical journal · 2016Article
- Retinal Conformation Changes Rhodopsin's Dynamic Ensemble.Biophysical journal · 2015Article
- Retinal Flips the Script.Biophysical journal · 2015Article
- Binding of the Antagonist Caffeine to the Human Adenosine Receptor hA2AR in Nearly Physiological Conditions.PloS one · 2015Article
- Concerted dynamic motions of an FABP4 model and its ligands revealed by microsecond molecular dynamics simulations.Biochemistry · 2014Article
- Article
- Conformational flexibility and structural dynamics in GPCR-mediated G protein activation: a perspective.Journal of molecular biology · 2013Review
- Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor.Journal of the American Chemical Society · 2013Article
- Ligand-dependent cholesterol interactions with the human A(2A) adenosine receptor.Chemistry and physics of lipids · 2013Article
- Predictions for cholesterol interaction sites on the A2A adenosine receptor.Journal of the American Chemical Society · 2012Article
- Elastic Network Models are Robust to Variations in Formalism.Journal of chemical theory and computation · 2012Article
Corrections and comments
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Authors and funding
2 authors.
Funding
Abstract
The G-protein-coupled receptors (GPCRs) are a ubiquitous family of signaling proteins of exceptional pharmacological importance. The recent publication of structures of several GPCRs cocrystallized with ligands of differing activity offers a unique opportunity to gain insight into their function. To that end, we performed microsecond-timescale simulations of the A(2A) adenosine receptor bound to either of two agonists, adenosine or UK432097. Our data suggest that adenosine is highly dynamic when bound to A(2A), in stark contrast to the case with UK432097. Remarkably, adenosine finds an alternate binding pose in which the ligand is inverted relative to the crystal structure, forming relatively stable interactions with helices I and II. Our observations suggest new experimental tests to validate our predictions and deepen our understanding of GPCR signaling. Overall, our data suggest an intriguing hypothesis: that the 100- to 1000-fold greater efficacy of UK432097 relative to adenosine arises because UK432097 stabilizes a much tighter neighborhood of active conformations, which manifests as a greater likelihood of G-protein activation per unit time.
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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.