7eu7 | pdb_00007eu7

Structure of the human GluN1-GluN2A NMDA receptor in complex with S-ketamine, glycine and glutamate

spinqualitylabelsall models 7eu7, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7eu7 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GLU, GLY, JC9, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease NMDZ1_HUMAN Defects in GRIN1 are the cause of mental retardation autosomal dominant type 8 (MRD8) [MIM:614254. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Function NMDZ1_HUMAN NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity). Publication Abstract from PubMed Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors(1). A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants(2,3). Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant(4). Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants. Structural basis of ketamine action on human NMDA receptors.,Zhang Y, Ye F, Zhang T, Lv S, Zhou L, Du D, Lin H, Guo F, Luo C, Zhu S Nature. 2021 Aug;596(7871):301-305. doi: 10.1038/s41586-021-03769-9. Epub 2021, Jul 28. PMID:34321660 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA