5L1H

AMPA subtype ionotropic glutamate receptor GluA2 in complex with noncompetitive inhibitor GYKI53655

Summary for 5L1H

• Entry DOI: 10.2210/pdb5l1h/pdb
• Related: 5L1B 5L1E 5L1F 5L1G
• Descriptor: Glutamate receptor 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, (8R)-5-(4-aminophenyl)-N,8-dimethyl-8,9-dihydro-2H,7H-[1,3]dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide (3 entities in total)
• Functional Keywords: transporter, membrane protein, transport protein, transport protein-inhibitor complex, transport protein/inhibitor
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 4
• Total formula weight: 361517.32

Authors

Yelshanskaya, M.V.,Singh, A.K.,Sampson, J.M.,Sobolevsky, A.I. (deposition date: 2016-07-29, release date: 2016-10-19, Last modification date: 2023-10-04)

Primary citation

Yelshanskaya, M.V.,Singh, A.K.,Sampson, J.M.,Narangoda, C.,Kurnikova, M.,Sobolevsky, A.I.
Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs.
Neuron, 91:1305-1315, 2016

PubMed 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.

PubMed: 27618672
DOI: 10.1016/j.neuron.2016.08.012

Experimental method

X-RAY DIFFRACTION (3.801 Å)