黑料吃瓜资源

Precisely mapped allosteric binding site will facilitate design of drugs with minimal side effects

Cold Spring Harbor, NY — Structural biologists at 黑料吃瓜资源 (CSHL) have obtained a precise molecular map of the binding site for an allosteric inhibitor in a subtype of the NMDA (N-methyl-D-aspartate) receptor, which is commonly expressed in brain cells.

The CSHL team used x-ray crystallography to obtain a very precise map of the structure of the amino terminal domain (ATD) of the GluN1b鈥揋luN2B subunits of the NMDA receptor, including its allosteric binding site. This view, at a resolution of 2.6A藲, shows the subunits docked with ifenprodil (grey spheres at the interface of the two subunits), a known allosteric inhibitor of the NMDA receptor.The newly discovered binding site—a docking port within the receptor—is important because it is a potential target for drugs that can modulate NMDA receptors, dysfunctions of which have been implicated in depression, schizophrenia, Parkinson鈥檚 and Alzheimer鈥檚 diseases as well as stroke-related brain injuries.

Allosteric sites in receptors are distinguished from their 鈥減rimary鈥� or 鈥渁ctive鈥� binding sites. Importantly, the newly obtained molecular map will enable scientists to design highly specific compounds that home in on the allosteric site, thereby minimizing 鈥渙ff-target effects,鈥� which give rise to a drug鈥檚 unwanted side effects.

In a study led by CSHL Associate Professor Hiro Furukawa and published June 15 in the journal Nature, the allosteric site of interest is shown to be in the region of NMDA receptors called the amino terminal domain. A class of allosteric inhibitors for NMDA receptors, called phenylethanolamines, has previously been identified. One such compound, ifenprodil, is known to bind specifically to the GluN1/GluN2B subtype of the NMDA receptor, but not to other subtypes.

The neuroprotective properties of phenylethanolamines have inspired scientists to employ them for treatment of neurological diseases and disorders.聽Some are now being tested in clinical trials for depression, pain, Parkinson鈥檚 disease, and Alzheimer鈥檚 disease.

The detailed blueprint of the allosteric site where phenylethanolamines bind to the receptor will facilitate rational design of improved compounds. In the work published on June 15th, Furukawa鈥檚 group identifies the precise binding site of phenylethanolamine within the amino terminal domain of GluN1/GluN2B NMDA receptors. The results were obtained through biochemistry and x-ray crystallography, a method that features exposing a crystalline form of the molecule under study to very high-energy x-ray beams, which reveals its features in great detail. This enabled the team to demonstrate that phenylethanolamine is recognized at the interface of the GluN1 and GluN2B subunits of the receptor, rather than at a previously predicted site within GluN2B.

鈥淏efore this study, we did not have a sufficiently precise map of NMDA receptor subunits to facilitate the design of better and more effective compounds that could dock at the allosteric site. Our results should move drug development in the right direction.聽We are now optimistic that the field can determine optimal ways of targeting NMDA receptors for therapeutic purposes,鈥� Furukawa says.

Written by: Peter Tarr, Senior Science Writer | [email protected] | 516-367-8455

Funding

This work was supported by NIH MH085926, the Alzheimer鈥檚 Association and a donation from the Fox family.聽Dr. Furukawa was also funded by a scientist development grant from the American Heart Association. Team member and co-author Erkan Karakas is supported by a NARSAD Lieber Young Investigator Award.

Citation

鈥淪ubunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors鈥� was published online ahead of print in Nature on June 15, 2011.聽 The authors are: Erkan Karakas, Noriko Simorowski and Hiro Furukawa.聽 The paper can be accessed at by using the following identifier: doi:10.1038/nature10180.