The UNC School of Medicine lab of Bryan L. Roth, MD, PhD, solved the high-resolution, complex structures of drug-like compounds bound to designer brain cell receptors, paving the way for the creation of next-generation chemogenetic tools. Postdoc Shicheng Zhang, PhD, led this research published in Nature.
Understanding of how neuronal activity modulates brain function is a key first step towards creating more effective drugs to treat a variety of neuropsychiatric illnesses, including depression, anxiety, schizophrenia, substance abuse, epilepsy, and others.
To both manipulate and understand this basic feature of neuronal biology, the lab of Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine, created a chemogenetic technology called DREADD – designer receptors exclusively activated by designer drugs – in the mid-2000s. Even though this technology is used ubiquitously in the neurosciences, why the technology was so efficient was unknown.
Now, as reported in the journal Nature, the Roth lab led by postdoctoral researcher Shicheng Zhang, PhD, used cryogenic electron microscopy to determine the detailed, high resolution structures of four DREADDs bound to three drug-like but inert compounds.
This work, made possible through the UNC CryoEM Core Facility, reveals key details of DREADDs that should accelerate the structure-guided discovery of next-generation chemogenetic tools.
“Although DREADDs are widely used, the precise molecular basis for why they are so useful has been obscure until now,” Zhang said. “We think these structures will help scientists around the world, including here at UNC-Chapel Hill, investigate the development of more effective and safer therapeutics for a host of neuropsychiatric conditions.”
Shicheng Zhang is the lead author of the paper. Other authors are senior author Bryan Roth, Ryan Gumpper, X-P Huang, Yongfeng Liu, Brian Krumm and Can Cao and former TarHeel Jonathan Fay from the University of Maryland School of Medicine.