2F34

Crystal Structure of the GluR5 Ligand Binding Core Dimer with UBP310 At 1.74 Angstroms Resolution

Summary for 2F34

• Entry DOI: 10.2210/pdb2f34/pdb
• Related: 1TXF 2F35 2F36
• Descriptor: GLUTAMATE RECEPTOR, IONOTROPIC KAINATE 1, CHLORIDE ION, PENTAETHYLENE GLYCOL, ... (5 entities in total)
• Functional Keywords: membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P22756
• Total number of polymer chains: 2
• Total formula weight: 59677.22

Authors

Mayer, M.L. (deposition date: 2005-11-18, release date: 2006-04-04, Last modification date: 2023-08-23)

Primary citation

Mayer, M.L.,Ghosal, A.,Dolman, N.P.,Jane, D.E.
Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists.
J.Neurosci., 26:2852-2861, 2006

PubMed Abstract: Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the mammalian CNS. Numerous crystallographic studies, the majority on the GluR2-subtype AMPA receptor, have revealed the structural basis for binding of subtype-specific agonists. In contrast, because there are far fewer antagonist-bound structures, the mechanisms for antagonist binding are much less well understood, particularly for kainate receptors that exist as multiple subtypes with a distinct biology encoded by the GluR5-7, KA1, and KA2 genes. We describe here high-resolution crystal structures for the GluR5 ligand-binding core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The crystal structures reveal the structural basis for the high selectivity for GluR5 observed in radiolabel displacement assays for the isolated ligand binding cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of glutamate-activated currents in studies on full-length ion channels. The antagonists bind via a novel mechanism and do not form direct contacts with the E723 side chain as occurs in all previously solved AMPA and kainate receptor agonist and antagonist complexes. This results from a hyperextension of the ligand binding core compared with previously solved structures. As a result, in dimer assemblies, there is a 22 A extension of the ion channel linkers in the transition from antagonist- to glutamate-bound forms. This large conformational change is substantially different from that described for AMPA receptors, was not possible to predict from previous work, and suggests that glutamate receptors are capable of much larger movements than previously thought.

PubMed: 16540562
DOI: 10.1523/JNEUROSCI.0123-06.2005

Experimental method

X-RAY DIFFRACTION (1.74 Å)