6FQK

GluA2(flop) S729C ligand binding core dimer bound to ZK200775 at 1.98 Angstrom resolution

Summary for 6FQK

• Entry DOI: 10.2210/pdb6fqk/pdb
• Descriptor: Glutamate receptor 2,Glutamate receptor 2, {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid (3 entities in total)
• Functional Keywords: ampar receptor, ligand binding domain, competitive antagonist, cross-linked dimer, membrane protein
• Biological source: Rattus norvegicus (Norway Rat); More
• Total number of polymer chains: 2
• Total formula weight: 61652.41

Authors

Coombs, I.D.,Soto, D.,Gold, M.G.,Farrant, M.F.,Cull-Candy, S.G. (deposition date: 2018-02-14, release date: 2019-03-13, Last modification date: 2024-10-23)

Primary citation

Coombs, I.D.,Soto, D.,McGee, T.P.,Gold, M.G.,Farrant, M.,Cull-Candy, S.G.
Homomeric GluA2(R) AMPA receptors can conduct when desensitized.
Nat Commun, 10:4312-4312, 2019

PubMed Abstract: Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors (AMPARs), which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we present evidence that homomeric Q/R-edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (γ-2, γ-8 or GSG1L), generates large fractional steady-state currents and anomalous current-variance relationships. Our results from fluctuation analysis, single-channel recording, and kinetic modeling, suggest that the steady-state current is mediated predominantly by conducting desensitized receptors. When combined with crystallography this unique functional readout of a hitherto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes.

PubMed: 31541113
DOI: 10.1038/s41467-019-12280-9

Experimental method

X-RAY DIFFRACTION (1.98010442598 Å)