PDBsum entry 5h8n

Transport protein

PDB id: 5h8n

Contents

Protein chains

276 a.a.

282 a.a.

Ligands

GLU

5YD

GLY

Metals

_CA

Waters ×138

PDB id:

5h8n

Name:

Transport protein

Title:

Structure of the human glun1/glun2a lbd in complex with nam

Structure:

Glutamate receptor ionotropic, nmda 2a,glutamate receptor ionotropic, nmda 2a. Chain: a. Fragment: unp residues 401-539, gt linker, unp residues 661-802. Synonym: glun2a, glutamate [nmda] receptor subunit epsilon-1, n- methyl d-aspartate receptor subtype 2a, hnr2a. Engineered: yes. Glutamate receptor ionotropic, nmda 1,glutamate receptor ionotropic, nmda 1.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grin2a, nmdar2a. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: grin1, nmdar1. Expression_system_taxid: 562

Resolution:

2.50Å R-factor: 0.182 R-free: 0.236

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 chain

Q12879  (NMDE1_HUMAN) -  Glutamate receptor ionotropic, NMDA 2A from Homo sapiens

Seq: 1464 a.a.

Struc: 276 a.a.

Protein chain

Q05586  (NMDZ1_HUMAN) -  Glutamate receptor ionotropic, NMDA 1 from Homo sapiens

Seq: 938 a.a.

Struc: 282 a.a.*

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

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.