Featured Research

from universities, journals, and other organizations

Scientists solve structure of NMDA receptor unit that could be drug target for neurological diseases

Date:
November 13, 2009
Source:
Cold Spring Harbor Laboratory
Summary:
Scientists report success in solving the molecular structure of a key portion of a cellular receptor implicated in Alzheimer's, Parkinson's and other serious illnesses.

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.

Assistant Professor Hiro Furukawa, Ph.D., and colleagues at CSHL, in cooperation with the National Synchrotron Light Source at Brookhaven National Laboratory, obtained crystal structures for one of several "subunits" of the NMDA receptor. This receptor, formally called the N-methyl-D-aspartate receptor, belongs to a family of cellular receptors that mediate excitatory nerve transmission in the brain.

Excitatory signals represent the majority of nerve signals in most regions of the human brain. One theory of causation in Alzheimer's, Parkinson's and multiple sclerosis posits that excessive amounts of the excitatory neurotransmitter, glutamate, can cause an overstimulation of glutamate receptors, including the NMDA receptor. Such excitotoxicity, the theory holds, can cause nerve-cell death and subsequent neurological dysfunction.

A class of inhibitors of the NMDA receptor under the generic name Memantine has been approved by the U.S. Food and Drug Administration for use in moderate and severe cases of Alzheimer's. Memantine is a non-specific inhibitor of the NMDA receptor and is neither a cure nor an agent that can halt progression of the disease. The search is well under way for molecules that can shut down the NMDA receptor with much greater specificity. The CSHL team's work pertains directly to that effort.

The NMDA receptor is modular, composed of 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. Furukawa's CSHL team focused on a portion of the so-called extracellular domain of the receptor, a subunit called NR2B, which includes a domain of particular interest called the ATD (the amino terminal domain).

"This part is of great interest to us because it has very little in common with ATDs in other kinds of glutamate receptors involved in nerve transmission," says Furukawa. Its uniqueness makes it a potentially interesting target for future drugs. "Our interest is even keener because we already know there are a rich spectrum of small molecules that can bind the ATD of NMDA receptors."

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.

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.


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. Karakas et al. Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. The EMBO Journal, 2009; DOI: 10.1038/emboj.2009.338

Cite This Page:

Cold Spring Harbor Laboratory. "Scientists solve structure of NMDA receptor unit that could be drug target for neurological diseases." ScienceDaily. ScienceDaily, 13 November 2009. <www.sciencedaily.com/releases/2009/11/091112095034.htm>.
Cold Spring Harbor Laboratory. (2009, November 13). Scientists solve structure of NMDA receptor unit that could be drug target for neurological diseases. ScienceDaily. Retrieved October 2, 2014 from www.sciencedaily.com/releases/2009/11/091112095034.htm
Cold Spring Harbor Laboratory. "Scientists solve structure of NMDA receptor unit that could be drug target for neurological diseases." ScienceDaily. www.sciencedaily.com/releases/2009/11/091112095034.htm (accessed October 2, 2014).

Share This



More Mind & Brain News

Thursday, October 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Pregnancy Spacing Could Have Big Impact On Autism Risks

Pregnancy Spacing Could Have Big Impact On Autism Risks

Newsy (Oct. 1, 2014) A new study says children born less than one year and more than five years after a sibling can have an increased risk for autism. Video provided by Newsy
Powered by NewsLook.com
Stopping School Violence

Stopping School Violence

Ivanhoe (Oct. 1, 2014) A trauma doctor steps out of the hospital and into the classroom to teach kids how to calmly solve conflicts, avoiding a trip to the ER. Video provided by Ivanhoe
Powered by NewsLook.com
Pineal Cysts: Debilitating Pain

Pineal Cysts: Debilitating Pain

Ivanhoe (Oct. 1, 2014) A tiny cyst in the brain that can cause debilitating symptoms like chronic headaches and insomnia, and the doctor who performs the delicate surgery to remove them. Video provided by Ivanhoe
Powered by NewsLook.com
Burning Away Brain Tumors

Burning Away Brain Tumors

Ivanhoe (Oct. 1, 2014) Doctors are 'cooking' brain tumors. Hear how this new laser-heat procedure cuts down on recovery time. Video provided by Ivanhoe
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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