2QS3 | pdb_00002qs3

Crystal structure of the GluR5 ligand binding core dimer in complex with UBP316 at 1.76 Angstroms resolution

PDB DOI: https://doi.org/10.2210/pdb2QS3/pdb

Classification: MEMBRANE PROTEIN
Organism(s): Rattus norvegicus
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2007-07-30 Released: 2008-08-05
Deposition Author(s): Alushin, G.M., Jane, D.E., Mayer, M.L.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.76 Å
R-Value Free:
0.218 (Depositor), 0.220 (DCC)
R-Value Work:
0.187 (Depositor), 0.190 (DCC)
R-Value Observed:
0.189 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.5 of the entry. See complete history.

Literature

ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.

Dargan, S.L., Clarke, V.R., Alushin, G.M., Sherwood, J.L., Nistico, R., Bortolotto, Z.A., Ogden, A.M., Bleakman, D., Doherty, A.J., Lodge, D., Mayer, M.L., Fitzjohn, S.M., Jane, D.E., Collingridge, G.L.

(2009) Neuropharmacology 56: 121-130

PubMed: 18789344 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1016/j.neuropharm.2008.08.016
Primary Citation of Related Structures:
2QS3

PubMed Abstract:
Kainate receptors (KARs) are involved in both NMDA receptor-independent long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses in the CA3 region of the hippocampus. However, the identity of the KAR subtypes involved remains controversial. Here we used a highly potent and selective GluK1 (formerly GluR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs in these synaptic processes. We confirmed that ACET is an extremely potent GluK1 antagonist, with a Kb value of 1.4+/-0.2 nM. In contrast, ACET was ineffective at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100 microM) and had no effect at GluK3 (formerly GluR7) when tested at 1 microM. The X-ray crystal structure of ACET bound to the ligand binding core of GluK1 was similar to the UBP310-GluK1 complex. In the CA1 region of hippocampal slices, ACET was effective at blocking the depression of both fEPSPs and monosynaptically evoked GABAergic transmission induced by ATPA, a GluK1 selective agonist. In the CA3 region of the hippocampus, ACET blocked the induction of NMDA receptor-independent mossy fibre LTP. To directly investigate the role of pre-synaptic GluK1-containing KARs we combined patch-clamp electrophysiology and 2-photon microscopy to image Ca2+ dynamics in individual giant mossy fibre boutons. ACET consistently reduced short-term facilitation of pre-synaptic calcium transients induced by 5 action potentials evoked at 20-25Hz. Taken together our data provide further evidence for a physiological role of GluK1-containing KARs in synaptic facilitation and LTP induction at mossy fibre-CA3 synapses.

Organizational Affiliation

MRC Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, UK. sheila.dargan@bristol.ac.uk

Macromolecule Content

Total Structure Weight: 59.83 kDa
Atom Count: 4,761
Modelled Residue Count: 502
Deposited Residue Count: 516
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Glutamate receptor, ionotropic kainate 1	A, B	258	Rattus norvegicus	Mutation(s): 1 Gene Names: Grik1, Glur5
UniProt
Find proteins for P22756 (Rattus norvegicus) Explore P22756 Go to UniProtKB: P22756
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P22756
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
UBE Query on UBE Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B]	E [auth A], H [auth B]	3-({3-[(2S)-2-amino-2-carboxyethyl]-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl}methyl)-5-phenylthiophene-2-carboxylic acid C₂₀ H₁₉ N₃ O₆ S LCZDCKMQSBGXAH-AWEZNQCLSA-N		Interactions Focus chain E [auth A] Focus chain H [auth B] Interactions & Density Focus chain E [auth A] Focus chain H [auth B]
1PE Query on 1PE Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth B] MOL2 format, chain D [auth A] MOL2 format, chain G [auth B] mmCIF format, chain D [auth A] mmCIF format, chain G [auth B]	D [auth A], G [auth B]	PENTAETHYLENE GLYCOL C₁₀ H₂₂ O₆ JLFNLZLINWHATN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain G [auth B] Interactions & Density Focus chain D [auth A] Focus chain G [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B] mmCIF format, chain C [auth A] mmCIF format, chain F [auth B]	C [auth A], F [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]