ArticleScientific reports2019
Reconstruction of apo A2A receptor activation pathways reveal ligand-competent intermediates and state-dependent cholesterol hotspots.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 36 citations in OpenAlex.
- Effects of Membrane Cholesterol on the Structure and Function of Selected Class A GPCRs─Challenges and Future Perspectives.Biochemistry · 2025Review
- Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD).eLife · 2025Article
- Balancing G protein selectivity and efficacy in the adenosine ANature chemical biology · 2025Article
- Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography.Nature communications · 2024Article
- Structural insights into the high basal activity and inverse agonism of the orphan receptor GPR6 implicated in Parkinson's disease.Science signaling · 2024Article
- Article
- How Neuromembrane Lipids Modulate Membrane Proteins: Insights from G-Protein-Coupled Receptors (GPCRs) and Receptor Tyrosine Kinases (RTKs).Cold Spring Harbor perspectives in biology · 2023Review
- Dual mechanisms of cholesterol-GPCR interactions that depend on membrane phospholipid composition.Structure (London, England : 1993) · 2023Article
- Molecular Biophysics of Class A G Protein Coupled Receptors-Lipids Interactome at a Glance-Highlights from the ABiomolecules · 2023Review
- Molecular Simulations and Drug Discovery of Adenosine Receptors.Molecules (Basel, Switzerland) · 2022Review
- Allosteric modulation of the adenosine AeLife · 2022Article
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- MD Simulations Revealing Special Activation Mechanism of Cannabinoid Receptor 1.Frontiers in molecular biosciences · 2022Article
- Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs.Frontiers in molecular biosciences · 2022Review
- Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2021Review
- The future of biomolecular simulation in the pharmaceutical industry: what we can learn from aerodynamics modelling and weather prediction. Part 1. understanding the physical and computational complexity of in silico drug design.Acta crystallographica. Section D, Structural biology · 2021Article
- Molecular insights into the biased signaling mechanism of the μ-opioid receptor.Molecular cell · 2021Article
- Structures and Dynamics of Native-State Transmembrane Protein Targets and Bound Lipids.Membranes · 2021Review
- Predictable cholesterol binding sites in GPCRs lack consensus motifs.Structure (London, England : 1993) · 2021Article
- Allosteric interactions in the parathyroid hormone GPCR-arrestin complex formation.Nature chemical biology · 2020Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, active state structures are scarce. Molecular dynamics (MD) simulations have been used to explore the conformational landscape of GPCRs. Efforts have been made to retrieve active state conformations starting from inactive structures, however to date this has not been possible without using an energy bias. Here, we reconstruct the activation pathways of the apo adenosine receptor (A2A), starting from an inactive conformation, by applying adaptive sampling MD combined with a goal-oriented scoring function. The reconstructed pathways reconcile well with experiments and help deepen our understanding of A2A regulatory mechanisms. Exploration of the apo conformational landscape of A2A reveals the existence of ligand-competent states, active intermediates and state-dependent cholesterol hotspots of relevance for drug discovery. To the best of our knowledge this is the first time an activation process has been elucidated for a GPCR starting from an inactive structure only, using a non-biased MD approach, opening avenues for the study of ligand binding to elusive yet pharmacologically relevant GPCR states.
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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.