PDBsum entry 5l1h

Transport protein/inhibitor

PDB id: 5l1h

Contents

Protein chains

773 a.a.

Ligands

NAG ×4

GYK ×4

PDB id:

5l1h

Name:

Transport protein/inhibitor

Title:

Ampa subtype ionotropic glutamate receptor glua2 in complex with noncompetitive inhibitor gyki53655

Structure:

Glutamate receptor 2. Chain: a, b, c, d. Fragment: unp residues 25-847, with deletions of 397-398, 402-405, 566-587. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2. Engineered: yes

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293 gnti.

Resolution:

3.80Å R-factor: 0.277 R-free: 0.292

Authors:

M.V.Yelshanskaya,A.K.Singh,J.M.Sampson,A.I.Sobolevsky

Key ref:

M.V.Yelshanskaya et al. (2016). Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs. Neuron, 91, 1305-1315. PubMed id: 27618672 DOI: 10.1016/j.neuron.2016.08.012

Date:

29-Jul-16 Release date: 19-Oct-16

Protein chains

P19491  (GRIA2_RAT) -  Glutamate receptor 2 from Rattus norvegicus

Seq: 883 a.a.

Struc: 773 a.a.*

* PDB and UniProt seqs differ at 12 residue positions (black crosses)

DOI no: 10.1016/j.neuron.2016.08.012

Neuron 91:1305-1315 (2016)

PubMed id: 27618672

Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs.

M.V.Yelshanskaya, A.K.Singh, J.M.Sampson, C.Narangoda, M.Kurnikova, A.I.Sobolevsky.

ABSTRACT

Excitatory neurotransmission plays a key role in epileptogenesis. Correspondingly, AMPA-subtype ionotropic glutamate receptors, which mediate the majority of excitatory neurotransmission and contribute to seizure generation and spread, have emerged as promising targets for epilepsy therapy. The most potent and well-tolerated AMPA receptor inhibitors act via a noncompetitive mechanism, but many of them produce adverse side effects. The design of better drugs is hampered by the lack of a structural understanding of noncompetitive inhibition. Here, we report crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors. The inhibitors bind to a novel binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains. We propose that the inhibitors stabilize the AMPA receptor closed state by acting as wedges between the transmembrane segments, thereby preventing gating rearrangements that are necessary for ion channel opening.