ArticleJournal of the American Chemical Society2014
A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 79 citations in OpenAlex.
- Deciphering the allosteric landscape of 5-HTPharmacological reports : PR · 2026Article
- Structural basis for ADAM17 activation by the iRhom1 pseudoprotease.Cell reports · 2026Article
- Biased Signaling in Psychedelic Action.Annual review of pharmacology and toxicology · 2026Review
- Biased signalingActa pharmaceutica Sinica. B · 2025Review
- 5-HTPharmacological reviews · 2025Review
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- Unraveling Activation-Related Rearrangements and Intrinsic Divergence from Ligand-Specific Conformational Changes of the Dopamine D3 and D2 Receptors.Journal of chemical information and modeling · 2024Review
- Unraveling activation-related rearrangements and intrinsic divergence from ligand-induced conformational changes of the dopamine D3 and D2 receptors.bioRxiv : the preprint server for biology · 2023Article
- Computational insights into ligand-induced G protein and β-arrestin signaling of the dopamine D1 receptor.Journal of computer-aided molecular design · 2023Article
- Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor.International journal of molecular sciences · 2023Article
- A Disposable Screen Printed Electrodes with Hexagonal Ni(OH)Micromachines · 2023Article
- Identification of Molecular Determinants in iRhoms1 and 2 That Contribute to the Substrate Selectivity of Stimulated ADAM17.International journal of molecular sciences · 2022Article
- "Selective" serotonin 5-HTBiochemical pharmacology · 2022Review
- Interacting binding insights and conformational consequences of the differential activity of cannabidiol with two endocannabinoid-activated G-protein-coupled receptors.Frontiers in pharmacology · 2022Article
- Overcoming Depression with 5-HTInternational journal of molecular sciences · 2021Review
- Ligand-Dependent Conformational Transitions in Molecular Dynamics Trajectories of GPCRs Revealed by a New Machine Learning Rare Event Detection Protocol.Molecules (Basel, Switzerland) · 2021Article
- MSA-Regularized Protein Sequence Transformer toward Predicting Genome-Wide Chemical-Protein Interactions: Application to GPCRome Deorphanization.Journal of chemical information and modeling · 2021Article
- Blockade of 5-Hydroxytryptamine 2A Receptor Attenuates Precipitation of Naloxone-Induced Withdrawal Symptoms in Opioid-Exposed Mice.Frontiers in behavioral neuroscience · 2021Article
- Article
- A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity.Science signaling · 2020Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT(2A)R) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT(2A)R is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT(2A)R agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT(2A)R interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. The findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT(2A)R activation.
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