ArticleBiochemistry2009
Mechanisms of antagonism of the GluR2 AMPA receptor: structure and dynamics of the complex of two willardiine antagonists with the glutamate binding domain.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- Mechanistic and Molecular Insights into Empagliflozin's Role in Ferroptosis and Inflammation Trajectories in Acetaminophen-Induced Hepatotoxicity.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Computational Investigation into the Interactions of Traditional Chinese Medicine Molecules of WenQingYin with GluR2.International journal of molecular sciences · 2017Article
- Structural dynamics of the glycine-binding domain of the N-methyl-D-aspartate receptor.The Journal of biological chemistry · 2015Article
- Thermodynamics and mechanism of the interaction of willardiine partial agonists with a glutamate receptor: implications for drug development.Biochemistry · 2014Article
- Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization.Journal of medicinal chemistry · 2013Article
- Role of conformational dynamics in α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor partial agonism.The Journal of biological chemistry · 2012Article
- The structure of (-)-kaitocephalin bound to the ligand binding domain of the (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamate receptor, GluA2.The Journal of biological chemistry · 2012Article
- Mechanism of AMPA receptor activation by partial agonists: disulfide trapping of closed lobe conformations.The Journal of biological chemistry · 2011Article
- Mechanisms of modal activation of GluA3 receptors.Molecular pharmacology · 2011Article
- Potent and selective inhibition of a single alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit by an RNA aptamer.The Journal of biological chemistry · 2011Article
- Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation.Current opinion in neurobiology · 2011Review
- The hidden energetics of ligand binding and activation in a glutamate receptor.Nature structural & molecular biology · 2011Article
- Medicinal chemistry of competitive kainate receptor antagonists.ACS chemical neuroscience · 2011Review
- Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists.Neuropharmacology · 2011Article
- Glutamate receptor ion channels: structure, regulation, and function.Pharmacological reviews · 2010Review
- Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA.Biochemistry · 2010Article
- Hydrophobic side chain dynamics of a glutamate receptor ligand binding domain.The Journal of biological chemistry · 2010Article
- Energy transfer ligands of the GluR2 ligand binding core.Biochemistry · 2010Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission. The development of selective antagonists for glutamate receptor subtypes is of interest in the treatment of a variety of neurological disorders. This study presents the crystal structure of the binding domain of GluR2 bound to two antagonists (UBP277 and UBP282) that are derivatives of the natural product, willardiine. The antagonists bind to one lobe of the protein with interactions similar to agonists. Interaction with the second lobe differs between the two antagonists, resulting in a different position of the uracil ring and different orientations of the bilobed structure. UBP277 binding produces a stable lobe orientation that is similar to the apo state, but the binding of UBP282 produces the largest hyperextension of the lobes yet reported for an AMPA receptor. The carboxyethyl (UBP277) and carboxybenzyl (UBP282) substituents in the N(3) position keep the lobes separated by a "foot-in-the-door" mechanism and the internal dynamics are minimal compared to the CNQX-bound form of the protein (which makes minimal contacts with one of the two lobes). In contrast to the antagonists CNQX and DNQX, UBP277 and UBP282 produce complexes with higher thermal stability, but affinities that are more than 100-fold lower. These structures support the idea that antagonism is associated with the overall orientation of the lobes rather than with specific interactions, and antagonism can rise either from specific interactions with both lobes ("foot-in-the-door" mechanism) or from the lack of extensive interactions with one of the two lobes.
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