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US researchers have used an X-ray technique to solve the molecular structure of a key portion of a cellular receptor implicated in Alzheimer's, Parkinson's, and other serious illnesses. Erkan Karakas, Noriko Simorowski, and Hiro Furukawa of the WM Keck Structural Biology Laboratory, at Cold Spring Harbor Laboratory, in Cold Spring Harbor, New York, have determined the structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. NMDA is a water-soluble amino acid derivative, methylated aspartic acid, and acts to stimulate the NMDA receptor, one of the body's ionotropic glutamate receptors. By doing so it mimics the action of the neurotransmitter glutamate on that receptor, but unlike glutamate, NMDA binds only to and regulates only the NMDA receptor. It is well known that communication between cells involves the release, detection, and uptake of small molecules and ions. This process of signal transduction is integral to complex patterns of growth and development in the cell. Interfering chemically with these processes can be used in some circumstances to control symptoms. For instance, these receptors mediate the majority of fast excitatory synaptic transmission in the mammalian brain and so controlling them in some way might be useful in treating Alzheimer's, Parkinson's, and other serious illnesses, that are linked to disturbances in the normal functioning of this receptor. A novel class of blocker of the NMDA receptor with the generic name Memantine has been approved by the US Food and Drug Administration for use in moderate and severe cases of Alzheimer's disease. Memantine is a non-specific inhibitor of the NMDA receptor but it is neither cure nor an agent that can halt progression of the disease. It exemplifies the fact that as with many aspects of the central nervous system, the solution to treating the symptoms of such disorders is not necessarily based on the simple administration of a receptor agonist or antagonist. The search is therefore underway to find molecules that can shut down the NMDA receptor with much greater sub-type specificity. Furukawa explains that one of the hallmarks for the function of NMDA receptors is that their ion channel activity is much more complicated than it might at first site appear. The modular NMDA receptor comprises multiple domains with distinct functional roles. Part of the receptor is lodged in the membrane of nerve cells and part juts out from the membrane. The receptor regulated by binding of modulator compounds to the extracellular amino-terminal domain (ATD), which is distinct from the target site for the natural ligand, the L-glutamate-binding domain. Furukawa's CSHL team focused on this portion of the receptor's extracellular domain of a subunit called NR2B. "The molecular basis for the ATD-mediated allosteric regulation has been enigmatic because of a complete lack of structural information on NMDA receptor ATDs," Furukawa and colleagues explain. They have now provided a new clue to this phenomenon by obtaining the crystal structures of ATD from the NR2B NMDA receptor subunit in two distinct states, one in which zinc is absent and the other in which zinc is bound to the system. The X-ray work was undertaken at the National Synchrotron Light Source at Brookhaven National Laboratory in Upton, New York on (X29 and X25 beamlines). "The structures reveal the overall clamshell-like architecture distinct from the non-NMDA receptor ATDs and molecular determinants for the zinc-binding site, ion-binding sites, and the architecture of the putative phenylethanolamine-binding site," the researchers explain. "This part is of great interest to us because it has very little in common with ATDs in other kinds or subunits of glutamate receptors involved in nerve transmission," explains Furukawa. Its uniqueness makes it a potentially relevant target for future drug development. "Our interest is even keener because we already know there is a rich spectrum of small molecules that can bind the ATD of NMDA receptors." Such compounds include phenylethanolamines which "have high efficacy and specificity and show some promise as neuroprotective agents without side effects seen in compounds that bind at the extracellular domain of other receptors," Furukawa adds. With the structure in hand, it should be possible to rationally design phenylethanolamine derivatives that precisely bind the ATD within the clamshell cleft.
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