8AYM

Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118

Summary for 8AYM

• Entry DOI: 10.2210/pdb8aym/pdb
• EMDB information: 15716
• Descriptor: Voltage-dependent calcium channel gamma-8 subunit, Isoform Flip of Glutamate receptor 1, Isoform Flip of Glutamate receptor 2, ... (8 entities in total)
• Functional Keywords: ampar, ion channels, neurotransmission, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 496127.81

Authors

Zhang, D.,Lape, R.,Shaikh, S.,Kohegyi, B.,Watson, J.F.,Cais, O.,Nakagawa, T.,Greger, I.H. (deposition date: 2022-09-02, release date: 2023-04-19, Last modification date: 2024-11-06)

Primary citation

Zhang, D.,Lape, R.,Shaikh, S.A.,Kohegyi, B.K.,Watson, J.F.,Cais, O.,Nakagawa, T.,Greger, I.H.
Modulatory mechanisms of TARP gamma 8-selective AMPA receptor therapeutics.
Nat Commun, 14:1659-1659, 2023

PubMed Abstract: AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.

PubMed: 36966141
DOI: 10.1038/s41467-023-37259-5

Experimental method

ELECTRON MICROSCOPY (3.3 Å)