8SS9

Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state)

Summary for 8SS9

• Entry DOI: 10.2210/pdb8ss9/pdb
• EMDB information: 40741 40742 40743 40744 40745 40746 40747 40748 40749 40750
• Descriptor: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera, 2-(6'-oxo-1'-phenyl[1',6'-dihydro[2,3'-bipyridine]]-5'-yl)benzonitrile, {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid, ... (7 entities in total)
• Functional Keywords: ampa receptor, neurotransmission, tarp gamma-5, perampanel, signaling protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 4
• Total formula weight: 474788.97

Authors

Gangwar, S.P.,Yen, L.Y.,Yelshanskaya, M.V.,Sobolevsky, A.I. (deposition date: 2023-05-08, release date: 2023-09-06, Last modification date: 2024-10-09)

Primary citation

Gangwar, S.P.,Yen, L.Y.,Yelshanskaya, M.V.,Korman, A.,Jones, D.R.,Sobolevsky, A.I.
Modulation of GluA2-gamma 5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2.
Nat.Struct.Mol.Biol., 30:1481-1494, 2023

PubMed Abstract: Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment.

PubMed: 37653241
DOI: 10.1038/s41594-023-01080-x

Experimental method

ELECTRON MICROSCOPY (2.72 Å)