PDBsum entry 5h8s

Transport protein

PDB id: 5h8s

Contents

Protein chains

259 a.a.

Ligands

GLU ×3

5YC ×2

CAC

Metals

_ZN ×6

Waters ×666

PDB id:

5h8s

Name:

Transport protein

Title:

Structure of the human glua2 lbd in complex with gne3419

Structure:

Glutamate receptor 2,glutamate receptor 2. Chain: a, c, b. Fragment: unp residues 413-527, gt linker, unp residues 653-796. Synonym: glur-2, ampa-selective glutamate receptor 2, glur-b, glur- k2, glutamate receptor ionotropic, ampa 2, glua2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gria2, glur2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.70Å R-factor: 0.176 R-free: 0.206

Authors:

H.J.A.Wallweber,P.J.Lupardus

Key ref:

D.H.Hackos et al. (2016). Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function. Neuron, 89, 983-999. PubMed id: 26875626 DOI: 10.1016/j.neuron.2016.01.016

Date:

23-Dec-15 Release date: 24-Feb-16

Protein chains

P42262  (GRIA2_HUMAN) -  Glutamate receptor 2 from Homo sapiens

Seq: 883 a.a.

Struc: 259 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1016/j.neuron.2016.01.016

Neuron 89:983-999 (2016)

PubMed id: 26875626

Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function.

D.H.Hackos, P.J.Lupardus, T.Grand, Y.Chen, T.M.Wang, P.Reynen, A.Gustafson, H.J.Wallweber, M.Volgraf, B.D.Sellers, J.B.Schwarz, P.Paoletti, M.Sheng, Q.Zhou, J.E.Hanson.

ABSTRACT

To enhance physiological function of NMDA receptors (NMDARs), we identified positive allosteric modulators (PAMs) of NMDARs with selectivity for GluN2A subunit-containing receptors. X-ray crystallography revealed a binding site at the GluN1-GluN2A dimer interface of the extracellular ligand-binding domains (LBDs). Despite the similarity between the LBDs of NMDARs and AMPA receptors (AMPARs), GluN2A PAMs with good selectivity against AMPARs were identified. Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices from wild-type (WT), but not GluN2A knockout (KO), mice. Individual GluN2A PAMs exhibited variable degrees of glutamate (Glu) dependence, impact on NMDAR Glu EC50, and slowing of channel deactivation. These distinct PAMs also exhibited differential impacts during synaptic plasticity induction. The identification of a new NMDAR modulatory site and characterization of GluN2A-selective PAMs provide powerful molecular tools to dissect NMDAR function and demonstrate the feasibility of a therapeutically desirable type of NMDAR enhancement.