Researchers from the University of Chicago have described the three-dimensional, atomic structure of an important cell receptor molecule linked to the development of several diseases, including melanoma, acute myeloid leukemia, and bilateral frontoparietal polymicrogyria, a debilitating developmental brain disorder. The study, published in the September 21, 2016 issue of Neuron, also describes an engineered protein molecule that turns off the receptor. The article is titled “Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains.” The report lays the groundwork for future development of pharmaceutical treatments that target the diseases mediated by these receptor proteins, called adhesion G-protein-coupled receptors, or aGPCRs. “Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combating diseases influenced by aGPCRs,” said Gabriel Salzman (photo), an M.D./Ph.D. student in the Biophysical Sciences Graduate Program at the University of Chicago. Over the past several years, research groups around the world have discovered a wide array of biological roles played by aGPCRs, many of which are closely linked to human diseases. Members of this group of receptors are closely related to more-widely studied, conventional GPCRs. The aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space, however, a structural foundation for understanding the function of these extracellular regions has been lacking.
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