Metabotropic Glutamate receptors (mGluRs) belong to the Family C of G-protein coupled receptors (GPCRs) and critically regulate neuronal excitability, synaptic transmission and plasticity through recognition of the amino acid and excitatory neurotransmitter glutamate. Many disorders of the CNS have been linked to alterations in neuronal excitability via the glutamatergic system. Accordingly, mGluRs have been the subject of an enormous drug discovery effort as they represent major therapeutic targets for treating numerous physiological dysfunctions and for neurodegenerative and neuropsychiatric conditions. Apart from the prototypical seven transmembrane helix (7TM) domain, mGluRs also include a large extracellular `venus fly trap' (VFT) domain that constitutes the glutamate binding site and a cysteine rich domain (CRD) that links the VFT to the 7TM. Binding of glutamate to the extracellular VFT domain triggers a large conformational change in the VFT domains from an open to a closed conformation. This clam-shell like closure of the extracellular domain results in receptor engagement and activation of G-proteins on the intracellular side of the transmembrane domain. Receptor activated G proteins then act to either enhance or repress secondary messenger signaling cascades. Despite intensive efforts, the mechanism of allosteric communication across the cell membrane by the mGluRs remains enigmatic due to the lack of structural information on full- length proteins. Here we propose to apply single-particle cryo-electron microscopy (cryo-EM) visualization in order to characterize the structure of mGluR5 and mGluR2 in activated and inactivated states and also in complex with their cognate G-proteins. The obtained structures will be used for molecular dynamics simulations aiming to unravel the molecular basis for conformational transitions coupled to signal instigation or silencing. Given that mGluRs are important drug targets for several CNS conditions including Parkinson's disease, Fragile X syndrome/autism spectrum disorders, schizophrenia, cognition, addiction, depression, anxiety and pain, the results obtained will have profound biomedical interest and will form the basis for the design of novel therapeutic strategies against neurological disorders.

Public Health Relevance

Glutamate is the single most important excitatory neurotransmitter of the central nervous system. The binding of glutamate to metabotropic glutamate receptors (mGluRs) results in a signaling cascade activation that starts with G protein binding to the intracellular side of the receptor. We propose to apply cryo- electron microscopy (cryo-EM) to characterize the structure of mGluR2 and mGluR5 in active and inactive states and in complex with their G protein partners. As defects in glutamatergic signaling are linked to many neurological conditions such as Parkinson's disease, Fragile X syndrome/autism spectrum disorders, schizophrenia, cognition, addiction, depression, anxiety and pain, this knowledge will be ultimately used for the design of novel therapeutic strategies to combat these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Silberberg, Shai D
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Stanford University
Schools of Medicine
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Liang, Yi-Lynn; Khoshouei, Maryam; Radjainia, Mazdak et al. (2017) Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546:118-123
Zhang, Yan; Sun, Bingfa; Feng, Dan et al. (2017) Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248-253