Featured Research

from universities, journals, and other organizations

Structural biologists reveal novel drug binding site in NMDA receptor subunit

Date:
June 17, 2011
Source:
Cold Spring Harbor Laboratory
Summary:
Structural biologists 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, dysfunctions of which have been implicated in depression, schizophrenia, Parkinson's and Alzheimer's diseases.

Structural biologists at Cold Spring Harbor Laboratory (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 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's and Alzheimer's diseases as well as stroke-related brain injuries.

Allosteric sites in neurotransmitters are distinguished from their "primary" or "active" 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 "off-target effects," which give rise to a drug's 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. Some are now being tested in clinical trials for depression, pain, Parkinson's disease, and Alzheimer's 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's 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.

"Before 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. We are now optimistic that the field can determine optimal ways of targeting NMDA receptors for therapeutic purposes," Furukawa says.

This work was supported by NIH MH085926, the Alzheimer's Association and a donation from the Fox family. 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.


Story Source:

The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.


Journal Reference:

  1. Erkan Karakas, Noriko Simorowski, Hiro Furukawa. Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature, 2011; DOI: 10.1038/nature10180

Cite This Page:

Cold Spring Harbor Laboratory. "Structural biologists reveal novel drug binding site in NMDA receptor subunit." ScienceDaily. ScienceDaily, 17 June 2011. <www.sciencedaily.com/releases/2011/06/110616092656.htm>.
Cold Spring Harbor Laboratory. (2011, June 17). Structural biologists reveal novel drug binding site in NMDA receptor subunit. ScienceDaily. Retrieved April 24, 2014 from www.sciencedaily.com/releases/2011/06/110616092656.htm
Cold Spring Harbor Laboratory. "Structural biologists reveal novel drug binding site in NMDA receptor subunit." ScienceDaily. www.sciencedaily.com/releases/2011/06/110616092656.htm (accessed April 24, 2014).

Share This



More Mind & Brain News

Thursday, April 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Study Says Most Crime Not Linked To Mental Illness

Study Says Most Crime Not Linked To Mental Illness

Newsy (Apr. 22, 2014) A new study finds most crimes committed by people with mental illness are not caused by symptoms of their illness or disorder. Video provided by Newsy
Powered by NewsLook.com
How Smaller Plates And Cutlery Could Make You Feel Fuller

How Smaller Plates And Cutlery Could Make You Feel Fuller

Newsy (Apr. 22, 2014) NBC's "Today" conducted an experiment to see if changing the size of plates and utensils affects the amount individuals eat. Video provided by Newsy
Powered by NewsLook.com
Do We Get Nicer With Age?

Do We Get Nicer With Age?

Newsy (Apr. 22, 2014) A recent report claims personality can change over time as we age, and usually that means becoming nicer and more emotionally stable. Video provided by Newsy
Powered by NewsLook.com
How to Master Motherhood With the Best Work/Life Balance

How to Master Motherhood With the Best Work/Life Balance

TheStreet (Apr. 22, 2014) In the U.S., there are more than 11 million couples trying to conceive at any given time. From helping celebrity moms like Bethanny Frankel to ordinary soon-to-be-moms, TV personality and parenting expert, Rosie Pope, gives you the inside scoop on mastering motherhood. London-born entrepreneur Pope is the creative force behind Rosie Pope Maternity and MomPrep. She explains why being an entrepreneur offers the best life balance for her and tips for all types of moms. Video provided by TheStreet
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins