Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein that is linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson’s, Alzheimer’s and autism.
“This receptor family is an exciting new target for future medicines for treatment of brain disorders,” said P. Jeffrey Conn, PhD, Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery, and senior co-author of the study at The Scripps Research Institute. “This new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts.”
The mGlu1 receptor helps regulate the neurotransmitter glutamate, and belongs to a family (superfamily) of molecules known as G protein-coupled receptors (GPCRs). GPCRs “sit” within the cell membrane and sense various molecules outside of the cell, including odors, hormones, neurotransmitters and light. After binding these molecules, GPCRs trigger a specific response inside the cell. Interestingly, more than one-third of therapeutic drugs target GPCRs—including allergy and heart medications, drugs that target the central nervous system and anti-depressants. This is something that not many who use these therapeutic drugs is aware of. Moreover, GPCRs are not well understood and many fundamental breakthroughs are now occurring due to the understanding of GPCRs as complex machines, carefully regulated by cholesterol and sodium.
Senior co-author of the study, Raymond Stevens, PhD, a professor in the Department of Integrative Structural and Computational Biology at TSRI leads a laboratorial team whose work revolves around structure and function of GPCRs. When the Stevens group started to look into the structure of mGlu1, it was a sure decision for them to reach out to researchers at Vanderbilt University, for Stevens states “They are the best in the world at understanding mGlu1 receptors. By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling.”
The collaboration between Vanderbilt and the Scripps team was an extraordinary combination for applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships.
The team decided to try to determine the structure of mGlu1 bound to novel “allosteric modulators” of mGlu1 contributed by the researchers of the Vanderbilt group. Allosteric modulators bind to a site that is far away from the binding site of the natural activator (in this case, presumably the glutamate molecule), but change the shape of the molecule enough to affect receptor function. Novel exhibition of structural biology in allosteric regulation and enzymatic activity. In the case of allosteric drug candidates, the hope is that the compounds affect the receptor function in a desirable, therapeutic way rather than a harmful way.
“Allosteric modulators are promising drug candidates as they can ‘fine-tune’ GPCR function,” said Karen Gregory, a former postdoctoral fellow at Vanderbilt University, now at Monash Institute of Pharmaceutical Sciences. “However, without a good idea of how drug-like compounds interact with the receptor to adjust the strength of the signal, discovery efforts are challenging.”
The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu1 in complex with one of the drug candidates, as well as a deeper understanding of the receptor’s function and pharmacology.
The 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.
“Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for the binding of allosteric modulators,” said Vsevolod “Seva” Katritch, assistant professor of molecular biology at TSRI and a co-author of the paper. “This is very important for understanding action of the allosteric modulator drugs and may partially explain difficulties in screening for such drugs. The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors,” he continued, “some of which are equally important in drug discovery.”
Source: Scripps Research Institute press release
Original Research: The research paper “Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator” appeared in Science on March 6.