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mGlu5 transmembrane domain structure clarified
07-09-2014
by Kelsey Kaustinen  |  Email the author
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LONDON & BOSTON—In a recent Nature study, Heptares Therapeutics has detailed the first high-resolution X-ray crystal structure of the transmembrane domain of the metabotropic glutamate receptor 5 (mGlu5), a Class C G-protein coupled receptor (GPCR).
 
As described on Nature’s Scitable page, GPCRs are “the largest and most diverse group of membrane receptors in eukaryotes. These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars and proteins. Such messages inform cells about the presence or absence of life-sustaining light or nutrients in their environment, or they convey information sent by other cells. GPCRs play a role in an incredible array of functions in the human body and … researchers estimate that between one-third and one-half of all marketed drugs act by binding to GPCRs.”
 
According to the Centre for Molecular Biology and Neuroscience at the University of Oslo, the neurotransmitter glutamate “is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function, including cognition, memory and learning.” Glutamate also regulates information related to cellular survival, differentiation and elimination, and formation and elimination of synapses, the site notes. A 2005 paper published in Nature Reviews Drug Discovery, titled “Metabotropic glutamate receptors as novel targets for anxiety and stress disorders,” noted that “G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms.”
 
According to the paper, “Various mGlu receptor subtypes, including group I (mGlu1 and mGlu5), group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu7 and mGlu8) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu2/3) receptors and antagonists for group I (in particular mGlu5) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress.”
 
Given the extent of its roles in neurological processes, mGlu5 has attracted a great deal of attention as a potential drug target for the treatment of diseases such as autism, fragile X syndrome, depression, addiction, anxiety and movement disorders. Thus far, structural studies of the neurotransmitter have primarily been focused on the extracellular domain.
 
“Heptares has now published pioneering research describing the use of its StaR platform for elucidating the structures of key members of all major GPCR families: A, B and C,” Fiona Marshall, chief scientific officer at Heptares, said in a press release. “These structures greatly enhance our ability to identify conserved and divergent structural and mechanistic features for each family and provide a strong basis for advancing structure-based drug discovery programs.”
 
This new paper details the crystal structure of mGlu5’s transmembrane domain in complex with the negative allosteric modulator (NAM) mavoglurant. The structure provides an in-depth look at the architecture of the transmembrane domain, including the precise location of the allosteric binding site and key micro-switches responsible for regulating receptor signaling. Using these new findings, Heptares has identified a number of novel differentiated mGlu5 NAM drug candidates that present with improved potency and pharmacokinetic properties compared to previous molecules. Additionally, given how related Class C GPCRs are, this new knowledge of mGlu5 is expected to aid in the design of both negative and positive allosteric modulators by offering a template for homology modeling of other Class C GPCRs.
 
Code: E07091403

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