Molecular organization of a zinc binding N-terminal modulatory domain in aNMDA 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 bacter ial periplasmic binding protein LIVBP. In NMDA receptors, the high-affinity Zn inhibition is eliminated by mutations in the LIVBP-like domain of the N R2A subunit. Using LIVBP structure, we have modeled this domain as two lobe s connected by a hinge and show that six residues controlling Zn inhibition form two clusters facing each other across a central cleft. Upon Zn bindin g the two lobes close tightly around the divalent cation. Thus, the extrace llular region of NR2A consists of a tandem of Venus flytrap domains, one bi nding the agonist and the other a modulatory ligand. Such a functional orga nization may apply to other eukaryotic iGluRs.