ArticleStructure (London, England : 1993)2015
Reduced curvature of ligand-binding domain free-energy surface underlies partial agonism at NMDA receptors.
Article in Structure (London, England : 1993), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 31 citations in OpenAlex.
- Structural basis of GluK2 kainate receptor activation by a partial agonist.Nature structural & molecular biology · 2025Article
- Evaluation of allosteric N-methyl-d-aspartate receptor modulation by GluN2A-selective antagonists using pharmacological equilibrium modeling.Molecular pharmacology · 2025Article
- Allosteric modulation of GluN1/GluN3 NMDA receptors by GluN1-selective competitive antagonists.The Journal of general physiology · 2023Article
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Structural biology and thermodynamics of GluD receptors.Neuropharmacology · 2021Review
- From bedside-to-bench: What disease-associated variants are teaching us about the NMDA receptor.The Journal of physiology · 2021Review
- Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation.Chemical reviews · 2020Review
- D-Serine Potently Drives Ligand-Binding Domain Closure in the Ionotropic Glutamate Receptor GluD2.Structure (London, England : 1993) · 2020Article
- NMDA Receptor Opening and Closing-Transitions of a Molecular Machine Revealed by Molecular Dynamics.Biomolecules · 2019Article
- Dissecting diverse functions of NMDA receptors by structural biology.Current opinion in structural biology · 2019Review
- Population Shift Mechanism for Partial Agonism of AMPA Receptor.Biophysical journal · 2019Article
- High Conformational Variability in the GluK2 Kainate Receptor Ligand-Binding Domain.Structure (London, England : 1993) · 2019Article
- Computer Simulations Predict High Structural Heterogeneity of Functional State of NMDA Receptors.Biophysical journal · 2018Article
- Structure, function, and allosteric modulation of NMDA receptors.The Journal of general physiology · 2018Review
- Glutamate and Glycine Binding to the NMDA Receptor.Structure (London, England : 1993) · 2018Article
- Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling.Biophysical journal · 2017Article
- Gating Motions and Stationary Gating Properties of Ionotropic Glutamate Receptors: Computation Meets Electrophysiology.Accounts of chemical research · 2017Review
- Computationally Discovered Potentiating Role of Glycans on NMDA Receptors.Scientific reports · 2017Article
- Advancing NMDA Receptor Physiology by Integrating Multiple Approaches.Trends in neurosciences · 2017Review
- NMDA Receptors in the Central Nervous System.Methods in molecular biology (Clifton, N.J.) · 2017Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
NMDA receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Partial agonists elicit submaximal channel activation, but crystal structures of the ligand-binding domains (LBDs) bound with partial and full agonists show little difference. To uncover the molecular mechanism for partial agonism, here we computed the free-energy surfaces of the GluN1 (an obligatory subunit of NMDA receptors) LBD bound with a variety of ligands. The free-energy minima are similarly positioned for full and partial agonists, but the curvatures are significantly reduced in the latter case, indicating higher probabilities for sampling conformations with a not fully closed domain cleft. The free-energy surfaces for antagonists have both shifted minima and further reduced curvatures. Reduced curvature of free-energy surface appears to explain well the partial agonism at NMDA receptors and may present a unique paradigm in producing graded responses for receptors in general.
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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.