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Structure paper

TitleChannel opening and gating mechanism in AMPA-subtype glutamate receptors.
Journal, issue, pagesNature, Vol. 549, Issue 7670, Page 60-65, Year 2017
Publish dateSep 7, 2017
AuthorsEdward C Twomey / Maria V Yelshanskaya / Robert A Grassucci / Joachim Frank / Alexander I Sobolevsky /
PubMed AbstractAMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the ...AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the neurotransmitter glutamate, AMPA receptors are critical for synaptic strength, and dysregulation of AMPA receptor-mediated signalling is linked to numerous neurological diseases. Here we use cryo-electron microscopy to solve the structures of AMPA receptor-auxiliary subunit complexes in the apo, antagonist- and agonist-bound states and determine the iris-like mechanism of ion channel opening. The ion channel selectivity filter is formed by the extended portions of the re-entrant M2 loops, while the helical portions of M2 contribute to extensive hydrophobic interfaces between AMPA receptor subunits in the ion channel. We show how the permeation pathway changes upon channel opening and identify conformational changes throughout the entire AMPA receptor that accompany activation and desensitization. Our findings provide a framework for understanding gating across the family of ionotropic glutamate receptors and the role of AMPA receptors in excitatory neurotransmission.
External linksNature / PubMed:28737760 / PubMed Central
MethodsEM (single particle)
Resolution4.2 - 6.8 Å
Structure data

EMDB-8819, PDB-5wek:
GluA2 bound to antagonist ZK and GSG1L in digitonin, state 1
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-8820, PDB-5wel:
GluA2 bound to antagonist ZK and GSG1L in digitonin, state 2
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-8821, PDB-5wem:
GluA2 bound to GSG1L in digitonin, state 1
Method: EM (single particle) / Resolution: 6.1 Å

EMDB-8822, PDB-5wen:
GluA2 bound to GSG1L in digitonin, state 2
Method: EM (single particle) / Resolution: 6.8 Å

EMDB-8823, PDB-5weo:
Activated GluA2 complex bound to glutamate, cyclothiazide, and STZ in digitonin
Method: EM (single particle) / Resolution: 4.2 Å

Chemicals

ChemComp-ZK1:
{[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / antagonist, medication*YM / Fanapanel

ChemComp-AJP:
Digitonin / detergent*YM / Digitonin

ChemComp-GLU:
GLUTAMIC ACID / Glutamic acid

ChemComp-CYZ:
CYCLOTHIAZIDE / Cyclothiazide

Source
  • rattus norvegicus (Norway rat)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Ion channel

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