Molecular organization of a zinc binding n-terminal modulatory domain in a NMDA receptor subunit.
Ionotropic glutamate receptors (iGluRs) bind agonists in a domain that has been crystallized and shown to have a bilobed structure. Eukaryotic iGluRs also possess a second extracellular N-terminal domain related to the bacterial periplasmic binding protein LIVBP. In NMDA receptors, the high-affinity Zn inhibition is eliminated by mutations in the LIVBP-like domain of the NR2A subunit. Using LIVBP structure, we have modeled this domain as two lobes connected by a hinge and show that six residues controlling Zn inhibition form two clusters facing each other across a central cleft. Upon Zn binding the two lobes close tightly around the divalent cation. Thus, the extracellular region of NR2A consists of a tandem of Venus flytrap domains, one binding the agonist and the other a modulatory ligand. Such a functional organization may apply to other eukaryotic iGluRs.
Paoletti
P
P
Laboratoire de Neurobiologie, CNRS UMR 8544, Ecole Normale Supérieure, 46 Rue d'Ulm, 75005, Paris, France. paoletti@biologie.ens.fr
Perin-Dureau
F
F
Fayyazuddin
A
A
Le Goff
A
A
Callebaut
I
I
Neyton
J
J
D000818:Animals; D001426:Bacterial Proteins; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000235:genetics; D003545:Cysteine / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins; D008024:Ligands; D008958:Models, Molecular; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021122:Protein Subunits; D011550:Pseudomonas aeruginosa / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000235:genetics; D014981:Xenopus; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D001426:Bacterial Proteins; D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D008024:Ligands; C488923:LivJ protein, E coli; C120997:NR2A NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C028332:leucine-isoleucine-valine binding protein, bacteria; D015032:Zinc; D003545:Cysteine