@article {49152,
	title = {Structural mechanism of functional modulation by gene splicing in NMDA receptors.},
	journal = {Neuron},
	volume = {98},
	year = {2018},
	month = {2018 Apr 10},
	pages = {521-9},
	abstract = {<p>Alternative gene splicing gives rise to N-methyl-D-aspartate (NMDA) receptor ion channels with defined functional properties and unique contributions to calcium signaling in a given chemical environment in the mammalian brain. Splice variants possessing the exon-5-encoded motif at the amino-terminal domain (ATD) of the GluN1 subunit are known to display robustly altered deactivation rates and pH sensitivity, but the underlying mechanism for this functional modification is largely unknown. Here, we show through cryoelectron microscopy (cryo-EM) that the presence of the exon 5 motif in GluN1 alters the local architecture of heterotetrameric GluN1-GluN2 NMDA receptors and creates contacts with the ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, which are absent in NMDA receptors lacking the exon 5 motif. The unique interactions established by the exon 5 motif are essential to the stability of the ATD/LBD and LBD/LBD interfaces that are critically involved in controlling proton sensitivity and deactivation.</p>
},
	issn = {1097-4199},
	doi = {10.1016/j.neuron.2018.03.034},
	author = {Regan, Michael C and Grant, Timothy and McDaniel, Miranda J and Karakas, Erkan and Zhang, Jing and Traynelis, Stephen F and Grigorieff, Nikolaus and Furukawa, Hiro}
}
@article {47509,
	title = {Activation of NMDA receptors and the mechanism of inhibition by ifenprodil.},
	journal = {Nature},
	volume = {534},
	year = {2016},
	month = {2016 Jun 2},
	pages = {63-8},
	abstract = {<p>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.</p>
},
	issn = {1476-4687},
	doi = {10.1038/nature17679},
	author = {Tajima, Nami and Karakas, Erkan and Grant, Timothy and Simorowski, Noriko and Diaz-Avalos, Ruben and Grigorieff, Nikolaus and Furukawa, Hiro}
}
