title: Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain.
abstract: Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors.
authors.affiliation: WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA.
authors.forename: Annabel
authors.initials: A
authors.lastname: Romero-Hernandez
authors.affiliation: WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Simorowski
authors.affiliation: WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Karakas
authors.affiliation: WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA. Electronic address: furukawa@cshl.edu.
authors.forename: Hiro
authors.initials: H
authors.lastname: Furukawa
mesh_terms: D015078:2-Hydroxyphenethylamine / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D003461:Crystallography; D006860:Hydrogen Bonding; D010880:Piperidines / Q000494:pharmacology; D020836:Protein Structure, Quaternary; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D061987:Sf9 Cells; D018411:Spodoptera; D014982:Xenopus laevis; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015078:2-Hydroxyphenethylamine; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D015032:Zinc; C121001:NR2B NMDA receptor; C010739:ifenprodil
keywords: N-methyl-D-aspartate receptors; amino-terminal domain; crystal structure; ifenprodil; ionotropic glutamate receptors; subtype specificity; zinc inhibition