title: NMDA receptor structures reveal subunit arrangement and pore architecture.
abstract: N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present X-ray crystal structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a ∼twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.
authors.affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2].
authors.forename: Chia-Hsueh
authors.initials: CH
authors.lastname: Lee
authors.affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2].
authors.forename: Wei
authors.initials: W
authors.lastname: Lü
authors.affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Jennifer Carlisle
authors.initials: JC
authors.lastname: Michel
authors.affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: April
authors.initials: A
authors.lastname: Goehring
authors.affiliation: Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Xianqiang
authors.initials: X
authors.lastname: Song
authors.affiliation: 1] Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Gouaux
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000737:chemistry; D007473:Ion Channels / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D010636:Phenols; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*; D014982:Xenopus laevis / Q000502:physiology*
chemical_list: D007473:Ion Channels; D008024:Ligands; D010636:Phenols; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D016291:Dizocilpine Maleate