Led by two-time NARSAD Grantee, P. Jeffrey Conn, Ph.D., Director of the Vanderbilt Center for Neuroscience Drug Discovery, scientists from The Scripps Research Institute and Vanderbilt University created a first-time detailed 3-D picture of a protein whose structure has remained largely a mystery to scientists. The mGlu1 receptor helps regulate the neurotransmitter glutamate and has been linked to mental illnesses such as schizophrenia and autism spectrum disorder.
"This receptor family is an exciting new target for future medicines for treatment of brain disorders," said Dr. Conn, senior author of the study. In a paper published March 6th in the journal Science, the team describes how they applied a combination of techniques, including X-ray crystallography, structural biology and molecular modeling to achieve a high-resolution image of the protein and gain a deeper understanding of the receptor's function and pharmacology.
The mGlu1 receptor helps belongs to a super-family of molecules known as G protein-coupled receptors (GPCRs). More than one-third of therapeutic medications target GPCRs, including allergy and heart medications as well as antidepressants.
mGlu1 has proven very difficult for researchers to study and there was no “template” from other related GPCR proteins to guide this team of researchers. They report that their findings show that mGlu1 possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance.
"The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors, some of which are equally important in drug discovery," explained Vsevolod Katritch, Ph.D., Assistant Professor of Molecular Biology at The Scripps Research Institute and a co-author of the paper.