ArticleBiochemistry2010
Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Positive AMPA and Kainate Receptor Modulators and Their Therapeutic Potential in CNS Diseases: A Comprehensive Review.International journal of molecular sciences · 2025Review
- Systemic increase of AMPA receptors associated with cognitive impairment of long COVID.Brain communications · 2025Article
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Imaging the glutamate synapse.Nature medicine · 2020Article
- 7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency.Journal of medicinal chemistry · 2018Article
- R/G editing in GluA2RScientific reports · 2017Article
- Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors.PloS one · 2017Article
- AMPA receptor potentiators: from drug design to cognitive enhancement.Current opinion in pharmacology · 2015Review
- Functional insight into development of positive allosteric modulators of AMPA receptors.Neuropharmacology · 2014Article
- Role of stoichiometry in the dimer-stabilizing effect of AMPA receptor allosteric modulators.ACS chemical biology · 2014Article
- Dynamics of cleft closure of the GluA2 ligand-binding domain in the presence of full and partial agonists revealed by hydrogen-deuterium exchange.The Journal of biological chemistry · 2013Article
- Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats.Psychopharmacology · 2013Article
- Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy.Neuropharmacology · 2013Article
- Functional insights from glutamate receptor ion channel structures.Annual review of physiology · 2013Review
- Experimental phasing using zinc anomalous scattering.Acta crystallographica. Section D, Biological crystallography · 2012Article
- The loss of an electrostatic contact unique to AMPA receptor ligand binding domain 2 slows channel activation.Biochemistry · 2012Article
- Subunit-selective allosteric inhibition of glycine binding to NMDA receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2012Article
- Structure and mechanism of glutamate receptor ion channel assembly, activation and modulation.Current opinion in neurobiology · 2011Review
- Glutamate receptor ion channels: where do all the calories go?Nature structural & molecular biology · 2011Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Glutamate receptors are important potential drug targets for cognitive enhancement and the treatment of schizophrenia in part because they are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system. One approach to the application of therapeutic agents to the AMPA subtype of glutamate receptors is the use of allosteric modulators, which promote dimerization by binding to a dimer interface thereby reducing the degree of desensitization and deactivation. AMPA receptors exist in two alternatively spliced variants (flip and flop) that differ in desensitization and receptor activation profiles. Most of the structural information about modulators of the AMPA receptor targets the flip subtype. We report here the crystal structure of the flop-selective allosteric modulator, PEPA, bound to the binding domains of the GluA2 and GluA3 flop isoforms of AMPA receptors. Specific hydrogen bonding patterns can explain the preference for the flop isoform. This includes a bidentate hydrogen bonding pattern between PEPA and N754 of the flop isoforms of GluA2 and GluA3 (the corresponding position in the flip isoform is S754). Comparison with other allosteric modulators provides a framework for the development of new allosteric modulators with preferences for either the flip or flop isoforms. In addition to interactions with N/S754, specific interactions of the sulfonamide with conserved residues in the binding site are characteristics of a number of allosteric modulators. These, in combination with variable interactions with five subsites on the binding surface, lead to different stoichiometries, orientations within the binding pockets, and functional outcomes.
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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.