PDBsum entry 5jty

Transport protein, receptor

PDB id: 5jty

Contents

Protein chains

262 a.a.

276 a.a.

Ligands

2JK

6ND

GLU

Waters ×81

PDB id:

5jty

Name:

Transport protein, receptor

Title:

Glutamate- and dcka-bound glun1/glun2a agonist binding domains with mpx-007

Structure:

Glutamate receptor ionotropic, nmda 1,glutamate receptor ionotropic, nmda 1. Chain: a. Fragment: unp residues 415-565. 684-821. Synonym: glun1,glutamate [nmda] receptor subunit zeta-1,n-methyl-d- aspartate receptor subunit nr1,nmd-r1,glun1,glutamate [nmda] receptor subunit zeta-1,n-methyl-d-aspartate receptor subunit nr1,nmd-r1. Engineered: yes. Glutamate receptor ionotropic, nmda 2a,glutamate receptor

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: grin1, nmdar1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: grin2a. Expression_system_taxid: 562

Resolution:

2.72Å R-factor: 0.230 R-free: 0.278

Authors:

T.-C.Mou,S.R.Sprang,K.B.Hansen

Key ref:

F.Yi et al. (2016). Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors. Neuron, 91, 1316-1329. PubMed id: 27618671 DOI: 10.1016/j.neuron.2016.08.014

Date:

10-May-16 Release date: 21-Sep-16

Protein chain

P35439  (NMDZ1_RAT) -  Glutamate receptor ionotropic, NMDA 1 from Rattus norvegicus

Seq: 938 a.a.

Struc: 262 a.a.*

Protein chain

Q00959  (NMDE1_RAT) -  Glutamate receptor ionotropic, NMDA 2A from Rattus norvegicus

Seq: 1464 a.a.

Struc: 276 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1016/j.neuron.2016.08.014

Neuron 91:1316-1329 (2016)

PubMed id: 27618671

Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors.

F.Yi, T.C.Mou, K.N.Dorsett, R.A.Volkmann, F.S.Menniti, S.R.Sprang, K.B.Hansen.

ABSTRACT

NMDA receptors mediate excitatory synaptic transmission and regulate synaptic plasticity in the central nervous system, but their dysregulation is also implicated in numerous brain disorders. Here, we describe GluN2A-selective negative allosteric modulators (NAMs) that inhibit NMDA receptors by stabilizing the apo state of the GluN1 ligand-binding domain (LBD), which is incapable of triggering channel gating. We describe structural determinants of NAM binding in crystal structures of the GluN1/2A LBD heterodimer, and analyses of NAM-bound LBD structures corresponding to active and inhibited receptor states reveal a molecular switch in the modulatory binding site that mediate the allosteric inhibition. NAM binding causes displacement of a valine in GluN2A and the resulting steric effects can be mitigated by the transition from glycine bound to apo state of the GluN1 LBD. This work provides mechanistic insight to allosteric NMDA receptor inhibition, thereby facilitating the development of novel classes NMDA receptor modulators as therapeutic agents.