9DHT

Desensitized state 2 of the GluA2-gamma2 complex

Summary for 9DHT

• Entry DOI: 10.2210/pdb9dht/pdb
• EMDB information: 46876
• Descriptor: Isoform Flip of Glutamate receptor 2, Voltage-dependent calcium channel gamma-2 subunit, GLUTAMIC ACID (3 entities in total)
• Functional Keywords: ligand-gated ion channel, ionotropic glutamate receptor, ampa receptor, ion channel, transport protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 8
• Total formula weight: 282873.24

Authors

Kumar Mondal, A.,Carrillo, E.,Jayaraman, V.,Twomey, E.C. (deposition date: 2024-09-04, release date: 2025-03-26, Last modification date: 2025-04-09)

Primary citation

Kumar Mondal, A.,Carrillo, E.,Jayaraman, V.,Twomey, E.C.
Glutamate gating of AMPA-subtype iGluRs at physiological temperatures.
Nature, 2025

PubMed Abstract: Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pore axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design and demonstrate how physiological temperatures can alter iGluR function.

PubMed: 40140570
DOI: 10.1038/s41586-025-08770-0

Experimental method

ELECTRON MICROSCOPY (4.31 Å)