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@ARTICLE{Larsen:861865,
author = {Larsen, Andreas Haahr and Dorosz, Jerzy and Thorsen, Thor
Seneca and Johansen, Nicolai Tidemand and Darwish, Tamim and
Midtgaard, Søren Roi and Arleth, Lise and Kastrup, Jette
Sandholm},
title = {{S}mall-angle neutron scattering studies on the {AMPA}
receptor {G}lu{A}2 in the resting, {AMPA}-bound and
{GYKI}-53655-bound states},
journal = {IUCrJ},
volume = {5},
number = {6},
issn = {2052-2525},
address = {Chester},
reportid = {FZJ-2019-02286},
pages = {780 - 793},
year = {2018},
abstract = {The AMPA receptor GluA2 belongs to the family of ionotropic
glutamate receptors, which are responsible for most of the
fast excitatory neuronal signalling in the central nervous
system. These receptors are important for memory and
learning, but have also been associated with brain diseases
such as Alzheimer's disease and epilepsy. Today, one drug is
on the market for the treatment of epilepsy targeting AMPA
receptors, i.e. a negative allosteric modulator of these
receptors. Recently, crystal structures and cryo-electron
microscopy (cryo-EM) structures of full-length GluA2 in the
resting (apo), activated and desensitized states have been
reported. Here, solution structures of full-length GluA2 are
reported using small-angle neutron scattering (SANS) with a
novel, fully matched-out detergent. The GluA2 solution
structure was investigated in the resting state as well as
in the presence of AMPA and of the negative allosteric
modulator GYKI-53655. In solution and at neutral pH, the
SANS data clearly indicate that GluA2 is in a compact form
in the resting state. The solution structure resembles the
crystal structure of GluA2 in the resting state, with an
estimated maximum distance (Dmax) of 179 ± 11 Å and a
radius of gyration (Rg) of 61.9 ± 0.4 Å. An ab initio
model of GluA2 in solution generated using DAMMIF clearly
showed the individual domains, i.e. the extracellular
N-terminal domains and ligand-binding domains as well as the
transmembrane domain. Solution structures revealed that
GluA2 remained in a compact form in the presence of AMPA or
GYKI-53655. At acidic pH only, GluA2 in the presence of AMPA
adopted a more open conformation of the extracellular part
(estimated Dmax of 189 ± 5 Å and Rg of 65.2 ±
0.5 Å), resembling the most open, desensitized class 3
cryo-EM structure of GluA2 in the presence of quisqualate.
In conclusion, this methodological study may serve as an
example for future SANS studies on membrane proteins.},
cin = {JCNS-FRM-II / Neutronenstreuung ; JCNS-1},
ddc = {530},
cid = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
I:(DE-Juel1)JCNS-1-20110106},
pnm = {6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623)
/ 6G15 - FRM II / MLZ (POF3-6G15)},
pid = {G:(DE-HGF)POF3-6G4 / G:(DE-HGF)POF3-6G15},
experiment = {EXP:(DE-MLZ)KWS1-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30443361},
UT = {WOS:000448982300014},
doi = {10.1107/S2052252518012186},
url = {https://juser.fz-juelich.de/record/861865},
}