PDBsum entry 4lz8

Transport protein

PDB id: 4lz8

Contents

Protein chains

258 a.a.

Ligands

GLU ×3

1YX ×2

Metals

_ZN ×5

Waters ×346

PDB id:

4lz8

Name:

Transport protein

Title:

Crystal structures of glur2 ligand-binding-domain in complex with glutamate and positive allosteric modulators

Structure:

Glutamate receptor 2. Chain: a, b, c. Fragment: see remark 999. Synonym: glur-2, ampa-selective glutamate receptor 2, glur-b, glur- k2, glutamate receptor ionotropic, ampa 2, glua2, ampa receptor. Engineered: yes. Mutation: yes

Source:

Rattus norvegicus. Brown rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.85Å R-factor: 0.198 R-free: 0.232

Authors:

J.Pandit

Key ref:

N.C.Patel et al. (2013). Discovery and characterization of a novel dihydroisoxazole class of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators. J Med Chem, 56, 9180-9191. PubMed id: 24215237 DOI: 10.1021/jm401274b

Date:

31-Jul-13 Release date: 04-Dec-13

Protein chains

P19491  (GRIA2_RAT) -  Glutamate receptor 2 from Rattus norvegicus

Seq: 883 a.a.

Struc: 258 a.a.*

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

DOI no: 10.1021/jm401274b

J Med Chem 56:9180-9191 (2013)

PubMed id: 24215237

Discovery and characterization of a novel dihydroisoxazole class of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators.

N.C.Patel, J.Schwarz, X.J.Hou, D.J.Hoover, L.Xie, A.J.Fliri, R.J.Gallaschun, J.T.Lazzaro, D.K.Bryce, W.E.Hoffmann, A.N.Hanks, D.McGinnis, E.S.Marr, J.L.Gazard, M.Hajós, R.J.Scialis, R.S.Hurst, C.L.Shaffer, J.Pandit, C.J.O'Donnell.

ABSTRACT

Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.