Wondering what the Daubert case law will look like in a few years as great new science pushes past epidemiology as new machines and techniques make cause and effect more or less directly observable ? Worried about Alzheimer’s perhaps being part of your future and wondering what’s ahead? Wondering why nations need to invest more n fundamental science at national laboratories such as Brookhaven and Argonne ? If any of those topics are in mind, consider reading a short article that reports on a new molecular level discovery made by scientists at the storied Cold Springs Harbor Laboratory using the National Synchrotron Light Source at Brookhaven National Laboratory. For the article online, go to ScienceDaily (Nov. 13, 2009). Key excerpts are below:
“A team of scientists at Cold Spring Harbor Laboratory (CSHL) reports on Thursday their success in solving the molecular structure of a key portion of a cellular receptor implicated in Alzheimer’s, Parkinson’s, and other serious illnesses
“Without a highly detailed molecular picture of the ATD, however, efforts to rationally design inhibitors cannot proceed. Hence the importance of Furukawa’s achievement: a crystal structure revealed by the powerful light source at Brookhaven National Laboratory, that shows the ATD to have a “clamshell”-like appearance that is important for its function. The results are published in a paper appearing online Thursday ahead of print in The EMBO Journal, the publication of the European Molecular Biology Organization. (emphasis added)
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.”