8VJ7
GluA2 bound to GYKI-52466 and Glutamate, Inhibited State 2
This is a non-PDB format compatible entry.
Summary for 8VJ7
| Entry DOI | 10.2210/pdb8vj7/pdb |
| EMDB information | 43276 |
| Descriptor | Isoform Flip of Glutamate receptor 2, GLUTAMIC ACID, 4-[(5S,8R)-8-methyl-6,7,8,9-tetrahydro-2H,5H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-5-yl]aniline (3 entities in total) |
| Functional Keywords | ligand gated ion channel, ionotropic glutamate receptor, allosteric inhibition, membrane protein, membrane protein-inhibitor complex, membrane protein/inhibitor |
| Biological source | Rattus norvegicus (Norway rat) |
| Total number of polymer chains | 4 |
| Total formula weight | 358693.64 |
| Authors | Hale, W.D.,Montano Romero, A.,Huganir, R.L.,Twomey, E.C. (deposition date: 2024-01-05, release date: 2024-06-05, Last modification date: 2025-05-28) |
| Primary citation | Hale, W.D.,Montano Romero, A.,Gonzalez, C.U.,Jayaraman, V.,Lau, A.Y.,Huganir, R.L.,Twomey, E.C. Allosteric competition and inhibition in AMPA receptors. Nat.Struct.Mol.Biol., 31:1669-1679, 2024 Cited by PubMed Abstract: Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases. PubMed: 38834914DOI: 10.1038/s41594-024-01328-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (4.85 Å) |
Structure validation
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