6usv
Crystal structure of GluN1/GluN2A ligand-binding domain in complex with glycine and SDZ 220-040Crystal structure of GluN1/GluN2A ligand-binding domain in complex with glycine and SDZ 220-040
Structural highlights
FunctionNMDE1_RAT NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits. Publication Abstract from PubMedExcitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 A or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology. Structural Basis of Functional Transitions in Mammalian NMDA Receptors.,Chou TH, Tajima N, Romero-Hernandez A, Furukawa H Cell. 2020 Jul 23;182(2):357-371.e13. doi: 10.1016/j.cell.2020.05.052. Epub 2020 , Jun 30. PMID:32610085[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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