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Activation of NMDA receptors and the mechanism of inhibition by ifenprodil

Tajima, Nami ; Karakas, Erkan ; Grant, Timothy ; Simorowski, Noriko ; Diaz-Avalos, Ruben ; Grigorieff, Nikolaus ; Furukawa, Hiro

Nature (London), 2016-06, Vol.534 (7605), p.63-68 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Activation of NMDA receptors and the mechanism of inhibition by ifenprodil
Autor: Tajima, Nami ; Karakas, Erkan ; Grant, Timothy ; Simorowski, Noriko ; Diaz-Avalos, Ruben ; Grigorieff, Nikolaus ; Furukawa, Hiro
Assuntos: Amino acids ; Animals ; Antagonists (Biochemistry) ; Apoproteins - chemistry ; Apoproteins - metabolism ; Apoproteins - ultrastructure ; BASIC BIOLOGICAL SCIENCES ; Brain research ; Cell receptors ; Chemical bonds ; Chemical inhibitors ; Cryoelectron Microscopy ; Crystal structure ; Crystallography, X-Ray ; Crystals ; Dosage and administration ; Electrophysiology ; Glutamate ; Health aspects ; Inhibition (Neurophysiology) ; Ion Channel Gating - drug effects ; Ion channels ; Ligands ; Membrane proteins ; Methyl aspartate ; Models, Molecular ; N-methyl-D-aspartate ; Neurological disorders ; Neurological research ; Neurotransmitters ; Physiological aspects ; Physiology ; Piperidines - pharmacology ; Protein Conformation - drug effects ; Protein Multimerization - drug effects ; Protein Subunits - chemistry ; Protein Subunits - metabolism ; Rats ; Receptors, N-Methyl-D-Aspartate - agonists ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate - chemistry ; Receptors, N-Methyl-D-Aspartate - metabolism ; Receptors, N-Methyl-D-Aspartate - ultrastructure ; Signal transduction ; Structure ; X-ray crystallography
É parte de: Nature (London), 2016-06, Vol.534 (7605), p.63-68
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Japan Society for the Promotion of Science (JSPS)
MH085926; GM105730
National Institutes of Health (NIH)
Robertson Research Fund of Cold Spring Harbor Laboratory
Stanley Institute of Cognitive Genomics
Burroughs Wellcome Fund Collaborative Research Travel Grant
Visiting Scientist program of the Janelia Research Center
Descrição: The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1-GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1-GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Activation of NMDA receptors and the mechanism of inhibition by ifenprodil

Tajima, Nami ; Karakas, Erkan ; Grant, Timothy ; Simorowski, Noriko ; Diaz-Avalos, Ruben ; Grigorieff, Nikolaus ; Furukawa, Hiro

England: Nature Publishing Group

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