- PDB-6ruq: Structure of GluA2cryst in complex the antagonist ZK200775 and th... -
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Basic information
Entry
Database: PDB / ID: 6ruq
Title
Structure of GluA2cryst in complex the antagonist ZK200775 and the negative allosteric modulator GYKI53655 at 4.65 A resolution
Components
Glutamate receptor 2GRIA2
Keywords
MEMBRANE PROTEIN / Receptor Negative allosteric modulator Antagonist Non-competitve antagonist
Function / homology
Function and homology information
spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / immunoglobulin binding / AMPA glutamate receptor complex ...spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / immunoglobulin binding / AMPA glutamate receptor complex / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / cellular response to glycine / asymmetric synapse / regulation of receptor recycling / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / positive regulation of synaptic transmission / presynaptic active zone membrane / glutamate-gated receptor activity / response to fungicide / regulation of synaptic transmission, glutamatergic / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor binding / cytoskeletal protein binding / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / SNARE binding / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / PDZ domain binding / protein tetramerization / postsynaptic density membrane / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / establishment of protein localization / receptor internalization / terminal bouton / cerebral cortex development / synaptic vesicle membrane / synaptic vesicle / presynapse / presynaptic membrane / signaling receptor activity / amyloid-beta binding / growth cone / scaffold protein binding / chemical synaptic transmission / perikaryon / postsynaptic membrane / dendritic spine / postsynaptic density / neuron projection / axon / neuronal cell body / glutamatergic synapse / synapse / dendrite / protein-containing complex binding / endoplasmic reticulum membrane / protein kinase binding / cell surface / endoplasmic reticulum / protein-containing complex / membrane / identical protein binding / plasma membrane Similarity search - Function
Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. ...Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I Similarity search - Domain/homology
Journal: FEBS J / Year: 2021 Title: Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2. Authors: Christian Krintel / Jerzy Dorosz / Andreas Haahr Larsen / Thor Seneca Thorsen / Raminta Venskutonytė / Osman Mirza / Michael Gajhede / Thomas Boesen / Jette Sandholm Kastrup / Abstract: Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: ...Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, noncompetitive (i.e., negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly results in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site. DATABASE: The atomic coordinates and structure factors from the crystal structure determination have been deposited in the Protein Data Bank under accession code https://doi.org/10.2210/pdb6RUQ/pdb. The electron microscopy 3D reconstruction volumes have been deposited in EMDB (EMD-4875: Apo; EMD-4920: ZK200775/GYKI53655; EMD-4921: AMPA compact; EMD-4922: AMPA/GYKI53655 bulgy; EMD-4923: GYKI53655; EMD-4924: AMPA bulgy; EMD-4925: AMPA/GYKI53655 compact).