PDBsum entry 2f35

Membrane protein

PDB id: 2f35

Contents

Protein chains

251 a.a. *

Ligands

1PE ×2

UBC ×2

Metals

_CL ×2

Waters ×416

* Residue conservation analysis

PDB id:

2f35

Name:

Membrane protein

Title:

Crystal structure of the glur5 ligand binding core with ubp302 at 1.87 angstroms resolution

Structure:

Glutamate receptor, ionotropic kainate 1. Chain: a, b. Fragment: glur5 ligand binding core (sequence database 446-559 and 682-821). Synonym: glutamate receptor 5, glur-5, glur5. Engineered: yes. Mutation: yes

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: grik1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.87Å R-factor: 0.193 R-free: 0.220

Authors:

M.L.Mayer

Key ref:

M.L.Mayer et al. (2006). Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci, 26, 2852-2861. PubMed id: 16540562

Date:

18-Nov-05 Release date: 04-Apr-06

Protein chains

P22756  (GRIK1_RAT) -  Glutamate receptor ionotropic, kainate 1 from Rattus norvegicus

Seq: 949 a.a.

Struc: 251 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

J Neurosci 26:2852-2861 (2006)

PubMed id: 16540562

Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists.

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

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.