The team obtained structures of the ATD domain with and without zinc binding to it. Zinc is a natural ligand that docks at a spot within the "clamshell" in routine functioning of the NMDA receptor. Of much greater interest is the location and nature of a suspected binding site of a small molecule type that is known to bind the ATD and inhibit the action of the NMDA receptor.

These inhibitor molecules are members of a class of compounds called 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 explains. Now that his team has solved the structure of the ATD domain of the NR2B subunit, it becomes possible to proceed with rational design of a phenylethanolamine-like compound that can precisely bind the ATD within what Furukawa and colleagues call its "clamshell cleft," based on the crystal structure they have obtained.

"Structure of the Zinc-bound Amino-terminal Domain of the NMDA receptor NR2B subunit" will be published online ahead of print November 12 in The EMBO Journal. The authors are: Erkan Karakas, Noriko Simorowski, and Hiro Furukawa. The paper will be available online Nov. 12 at: nature/emboj/journal/vaop/ncurrent/index.html

Source: Cold Spring Harbor Laboratory