PDBsum entry 2f35

Membrane protein

PDB id: 2f35

Contents

Protein chains

251 a.a.

Ligands

1PE ×2

UBC ×2

Metals

_CL ×2

Waters ×416

References listed in PDB file

Key reference

Title

Crystal structures of the kainate receptor glur5 ligand binding core dimer with novel glur5-Selective antagonists.

Authors

M.L.Mayer, A.Ghosal, N.P.Dolman, D.E.Jane.

Ref.

J Neurosci, 2006, 26, 2852-2861.

PubMed id

16540562

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.

Secondary reference #1

Title

Crystal structures of the glur5 and glur6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.

Author

M.L.Mayer.

Ref.

Neuron, 2005, 45, 539-552. [DOI no: 10.1016/j.neuron.2005.01.031]

PubMed id

15721240

Figure 4.
Figure 4. Docking GluR5-Selective Ligands in the GluR6 and GluR5 Ligand Binding Sites

Figure 7.
Figure 7. Interdomain Contacts in GluR5 and GluR2

The above figures are reproduced from the cited reference with permission from Cell Press