![]() The class of receptors from which DREADDs originated are often the intended targets of many therapeutics. We could see that shape of the space changed as well, contributing to why the new drugs fit better," said Dr. "With this imaging technique, we could see that the genetic changes in the DREADDs opened up the space where the memory molecule normally binds, allowing the new designer drugs to slip in. By changing two of the natural receptor's building blocks, the engineered DREADD receptor binds better to its own laboratory-designed drugs rather than to the original memory molecule-a process they visualized through their experiments. ![]() The original brain receptor, found in the cell membrane of neurons, traditionally binds to a molecule involved in learning and memory. The researchers also compared the structure of the natural brain receptor from which DREADDs originated to see how it differed from DREADDs. The researchers observed inhibitory (turning off cell functions) or stimulatory (turning on cell functions) DREADD receptors bound to each of two different designer drugs. This technique allowed researchers to determine the DREADD's structure when other older molecular imaging methods failed. This process flash-freezes the DREADDs in a way that does not form traditional ice crystals, but instead creates a sort of slurry that allows some movement in the molecules. Credit: Ryan Gumpper, UNCįor this new study, researchers used a newer imaging technology, known as cryogenic electron microscopy, to determine the molecular structure of DREADD receptors with the drugs. Three DREADD receptors (cream left panels duplicated in each video) with three different designer drugs bound. Scientists there designed these receptor proteins to react only to uniquely designed drugs that are pharmacologically inert because they only bind to the DREADD protein receptor. Hundreds of labs around the world now use the DREADD tool, which was developed at UNC. We were previously limited in how to upgrade their designs because we didn't fully understand how they worked at the structural level." "This knowledge will allow this tool to be further refined and optimized. "These findings provide atomic clarity into the nature of DREADD receptors bound to their drugs, resulting from the culmination of all these technologies converging at the right place and right time," said study author Jonathan Fay, Ph.D., Assistant Professor of Biochemistry and Molecular Biology at UMSOM. The research team published their findings in a recent issue of Nature. This step ultimately will bring them closer to an elusive goal-understanding the underpinnings of brain disorders, such as schizophrenia, substance abuse, epilepsy, and Alzheimer's, in order to develop more effective drugs to treat them. Now, a University of Maryland School of Medicine researcher and his colleagues at the University of North Carolina Chapel Hill (UNC) have unveiled the structure of these DREADDs that will pave the way for creating the next generation of these tools. DREADDs can enable researchers to turn specific cell functions on or off to examine groups of neurons in circuits more precisely. When introduced to a nerve cell or neuron, DREADDs acts like a specialized lock that only works when a key-in the form of a synthetic designer drug-fits into that lock.
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