PDBsum entry 5i2n

Transport protein

PDB id: 5i2n

Contents

Protein chains

277 a.a.

282 a.a.

Ligands

GLU

67J

EPE

GLY

Metals

_CA

Waters ×295

PDB id:

5i2n

Name:

Transport protein

Title:

Structure of the human glun1/glun2a lbd in complex with n-ethyl-7-{[2- fluoro-3-(trifluoromethyl)phenyl]methyl}-2-methyl-5-oxo-5h-[1, 3]thiazolo[3,2-a]pyrimidine-3-carboxamide (compound 29)

Structure:

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. Chain: b. Fragment: unp residues 415-565, gt linker, unp residues 684-821.

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:

2.12Å R-factor: 0.188 R-free: 0.223

Authors:

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

Key ref:

M.Volgraf et al. (2016). Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design. J Med Chem, 59, 2760-2779. PubMed id: 26919761 DOI: 10.1021/acs.jmedchem.5b02010

Date:

09-Feb-16 Release date: 16-Mar-16

Protein chain

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

Seq: 1464 a.a.

Struc: 277 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: 10.1021/acs.jmedchem.5b02010

J Med Chem 59:2760-2779 (2016)

PubMed id: 26919761

Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.

M.Volgraf, B.D.Sellers, Y.Jiang, G.Wu, C.Q.Ly, E.Villemure, R.M.Pastor, P.W.Yuen, A.Lu, X.Luo, M.Liu, S.Zhang, L.Sun, Y.Fu, P.J.Lupardus, H.J.Wallweber, B.M.Liederer, G.Deshmukh, E.Plise, S.Tay, P.Reynen, J.Herrington, A.Gustafson, Y.Liu, A.Dirksen, M.G.Dietz, Y.Liu, T.M.Wang, J.E.Hanson, D.Hackos, K.Scearce-Levie, J.B.Schwarz.

ABSTRACT

The N-methyl-d-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization.