抖阴黄版下载

Proteins are constantly performing a kind of dance. They move and contort their bodies to fulfill specific functions inside our bodies. The NMDAR protein executes an especially hard dance routine in our brains. One wrong step can lead to a range of neurological disorders. NMDAR binds to the neurotransmitter, glutamate, and another compound, glycine. These bindings control NMDAR鈥檚 dance steps. When their routine is over, the NMDAR opens. This open ion channel generates electrical signals critical for cognitive functions like memory.

The problem is that scientists couldn鈥檛 figure out the last step in NMDAR鈥檚 routine鈥攗ntil now. 抖阴黄版下载 Professor Hiro Furukawa and his team have deciphered the critical dance move in which NMDAR rotates into an open formation. In other words, they鈥檝e learned the NMDAR 鈥淭wist.鈥�

CSHL Professor Hiro Furukawa has long been interested in the NMDAR protein. In this episode of our podcast, he discusses a 2020 study that began to show how the NMDAR opens.

To capture this key step, Furukawa and his team used a technique called electron cryo-microscopy (cryo-EM), which freezes and visualizes proteins in action. First, the team had to find a way to keep a type of NMDAR called GluN1-2B in its open pose long enough to image it. So, Furukawa teamed up with Professors Stephen Traynelis and Dennis Liotta at Emory University. Together, they discovered a molecule that favors NMDAR in an open position.

鈥淚t鈥檚 not the most stable conformation,鈥� Furukawa explains. 鈥淭丑别re are many pieces dancing independently in NMDAR. They have to coordinate with each other. Everything has to go perfectly to open the ion channel. We need a precise amount of electrical signals at the right time for proper behaviors and cognitions.鈥�

The cryo-EM images allow researchers to see precisely how the NMDAR鈥檚 atoms move during its 鈥淭wist.鈥� This may one day lead to drug compounds that can teach the correct moves to NMDARs that have lost a step. Better drugs that target NMDARs might have applications for neurological disorders like Alzheimer鈥檚 and depression. Furukawa explains:

鈥淐ompounds bind to pockets within proteins and are imperfect, initially. This will allow us and chemists to find a way to fill those pockets more perfectly. That would improve the potency of the drug. Also, the shape of the pocket is unique. But there could be something similarly shaped in other proteins. That would cause side effects. So, specificity is key.鈥�

Indeed, there are many types of NMDARs in the brain. Another recent study from Furukawa鈥檚 lab offers the first view of the . Surprisingly, its dance moves are completely different. This routine results in unusual patterns of electrical signals.

In other words, we鈥檙e mastering the Twist. Next up: the headspin.

Written by: Luis Sandoval, Communications Specialist | sandova@cshl.edu | 516-367-6826

Funding

National Institutes of Health, Austin鈥檚 Purpose, Robertson Research Fund, Doug Fox Alzheimer鈥檚 Fund, Heartfelt Wings Foundation, Gertrude and Louis Feil Family Trust

Citation

Chou, T. H., et al., 鈥淢olecular Mechanism of ligand-gating and opening of NMDA receptor channel鈥�, Nature, July 31, 2024. DOI:

Michalski K., Furukawa, H., 鈥淪tructure and function of GluN1-3A NMDA receptor excitatory glycine receptor channel,鈥� Science Advances, April 12, 2024. DOI:

Core Facilites

鈥淭丑别 Electron Cryomicroscopy (Cryo-EM) Facility offers researchers access to cutting-edge technology that has made it possible to visualize complex biological systems at near atomic resolution and detail, providing novel molecular insight into human biology and disease.鈥� 鈥� Cryo-EM Facility Manager Dennis Thomas