Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins*
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Binding Sites / genetics
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Carrier Proteins / genetics
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Cells, Cultured
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Conserved Sequence / genetics
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Cysteine / metabolism
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Escherichia coli / genetics
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Escherichia coli Proteins*
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Ligands
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Models, Molecular
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Oocytes / cytology
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Oocytes / metabolism
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Protein Structure, Tertiary / drug effects
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Protein Subunits*
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Pseudomonas aeruginosa / genetics
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / chemistry
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Reproducibility of Results
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Sequence Alignment
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
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Substrate Specificity / genetics
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Xenopus
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Zinc / metabolism*
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Zinc / pharmacology
Substances
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Bacterial Proteins
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Carrier Proteins
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Escherichia coli Proteins
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Ligands
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LivJ protein, E coli
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NR2A NMDA receptor
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Protein Subunits
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Receptors, N-Methyl-D-Aspartate
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leucine-isoleucine-valine binding protein, bacteria
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Zinc
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Cysteine