PDBsum entry 4nf5

Transport protein, receptor

PDB id: 4nf5

Contents

Protein chains

272 a.a.

273 a.a.

Ligands

GLY

GOL ×3

2JJ

Waters ×619

PDB id:

4nf5

Name:

Transport protein, receptor

Title:

Crystal structure of glun1/glun2a ligand-binding domain in complex with glycine and d-ap5

Structure:

Glutamate receptor ionotropic, nmda 1. Chain: a. Fragment: unp residues 393-543. Unp residues 663-800. Synonym: glun1, glutamate [nmda] receptor subunit zeta-1, n-methyl-d- aspartate receptor subunit nr1, nmd-r1. Engineered: yes. Glutamate receptor ionotropic, nmda 2a. Chain: b. Fragment: unp residues 402-539. Unp residues 661-802.

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:

1.90Å R-factor: 0.173 R-free: 0.213

Authors:

A.Jespersen,N.Tajima,H.Furukawa

Key ref:

A.Jespersen et al. (2014). Structural insights into competitive antagonism in NMDA receptors. Neuron, 81, 366-378. PubMed id: 24462099 DOI: 10.1016/j.neuron.2013.11.033

Date:

30-Oct-13 Release date: 12-Mar-14

Protein chain

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

Seq: 938 a.a.

Struc: 272 a.a.*

Protein chain

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

Seq: 1464 a.a.

Struc: 273 a.a.*

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

DOI no: 10.1016/j.neuron.2013.11.033

Neuron 81:366-378 (2014)

PubMed id: 24462099

Structural insights into competitive antagonism in NMDA receptors.

A.Jespersen, N.Tajima, G.Fernandez-Cuervo, E.C.Garnier-Amblard, H.Furukawa.

ABSTRACT

There has been a great level of enthusiasm to downregulate overactive N-methyl-D-aspartate (NMDA) receptors to protect neurons from excitotoxicity. NMDA receptors play pivotal roles in basic brain development and functions as well as in neurological disorders and diseases. However, mechanistic understanding of antagonism in NMDA receptors is limited due to complete lack of antagonist-bound structures for the L-glutamate-binding GluN2 subunits. Here, we report the crystal structures of GluN1/GluN2A NMDA receptor ligand-binding domain (LBD) heterodimers in complex with GluN1- and GluN2-targeting antagonists. The crystal structures reveal that the antagonists, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and 1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), have discrete binding modes and mechanisms for opening of the bilobed architecture of GluN2A LBD compared to the agonist-bound form. The current study shows distinct ways by which the conformations of NMDA receptor LBDs may be controlled and coupled to receptor inhibition and provides possible strategies to develop therapeutic compounds with higher subtype-specificity.