BOSTONCarnegie Mellon University chemists have solved a decade-long molecular mystery that could eventually help scientists develop drug therapies to treat a variety of disorders, including epilepsy and Alzheimers disease. Using intensive theoretical and computational calculations, Carnegie Mellon researchers have modeled the initial molecular changes that occur when the neurotransmitter glutamate docks with a receptor on a neuron, which sets in motion a chain of events that culminates in the neuron firing an electrical impulse.
Tatyana Mamonova, a postdoctoral fellow in Assistant Professor Maria Kurnikovas laboratory at Carnegie Mellon, will present this report Wednesday, Aug. 22 at the 234th national meeting of the American Chemical Society in Boston.
Glutamate receptors, which are proteins found in neurons, form a channel through the neurons membrane. When glutamate, a signaling molecule released by other neurons, docks with the glutamate receptor, it causes a series of molecular shape changes that eventually open the channel and excite the neuron. Although the structure of the glutamate receptors docking site was known, no one knew precisely which atomic interactions between glutamate and the receptor caused the receptor to change its conformation until now.
The docking site (or ligand binding domain) closes when glutamate binds to it. Tatyana found two key electrostatic interactions that lock the ligand-binding site in its closed form once the ligand is bound, said Kurnikova. With this knowledge in hand, we can now model binding-site closure and opening using a computer.
Being able to simulate this conformational change is critical to understanding how binding regulates the protein channel, Kurnikova added. Ultimately, we could use the computer model to design a drug that either inhibits or enhances the activity of the glutamate receptor. Typically, pharmaceutical companies may scan hundreds of potential drugs to find
|Contact: Amy Pavlak|
Carnegie Mellon University