Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations

Nasrallah, Chady; Cannone, Giuseppe; Briot, Julie; Rottier, Karine; Berizzi, Alice E.; Huang, Chia-Ying; Quast, Robert B.; Hoh, François; Banères, Jean-Louis; Malhaire, Fanny; Berto, Ludovic; Dumazer, Anaëlle; Font, Joan; Gómez‐Santacana, Xavier; Catena, Juan Lorenzo; Kniazeff, Julie; Goudet, Cyril; Llebaría, Amadeu; Pin, Jean‐Philippe; Vinothkumar, Kutti R.; Lebon, Guillaume

doi:10.1016/j.celrep.2021.109648

Cited by 35 publications

(55 citation statements)

References 69 publications

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“…Based on structural (Doré et al, 2014; Du et al, 2021; Seven et al, 2021; Wu et al, 2014) and mutagenesis (Farinha et al, 2015; Gregory & Conn, 2015; Lundström et al, 2011) studies, the primary mGluR allosteric binding sites were determined to be located within the 7TM domain bundles. Previous work examining allosteric modulation of mGluR conformational dynamics generally used ensemble methods and was focused on the dimeric rearrangement of either the 7TM domain (Gutzeit et al, 2019; Nasrallah et al, 2021) or the extracellular ligand-binding domain (Cao et al, 2021). While these studies of individual domains provide insights into how allosteric modulators affect mGluR structure and dynamics, they are not conducive for the broader fingerprinting of the modulator effect across multiple domains of the receptor.…”

Section: Introductionmentioning

confidence: 99%

Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2

Liauw

Foroutan

Schamber

et al. 2022

Preprint

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Activation of G protein-coupled receptors (GPCRs) is an allosteric process. It involves conformational coupling between the orthosteric ligand binding site and the G protein binding site. Factors that bind at sites other than the orthosteric ligand binding site and alter this allosteric activation process are allosteric modulators and are important class of therapeutics. For many receptors, how modulation of signaling is represented at the structural level is unclear. Here, we developed FRET sensors to quantify receptor modulation at each of the three structural domains of metabotropic glutamate receptor 2 (mGluR2). We identified the conformational fingerprint for several allosteric modulators in live cells. This approach enabled us to derive a receptor-centric representation of allosteric modulation and to correlate structural modulation to the standard signaling modulation metrics. Single-molecule FRET analysis revealed that a NAM increases the occupancy of one of the intermediate states while a PAM increases the occupancy of the active state. Moreover, we found that the effect of allosteric modulators on the receptor dynamics is complex and depend on the orthosteric ligand. Collectively, our findings provide a structural mechanism of allosteric modulation in mGluR2 and suggest possible strategies for design of future modulators.

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Section: Introductionmentioning

confidence: 99%

Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2

Liauw

Foroutan

Schamber

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Unlike the other GPCR classes, the majority of the cryo-EM structures of class C GPCRs are not bound by transducers; albeit, recent work has also resolved G protein bound structures of members of this subfamily. , Class C GPCRs form homo- or heterodimers and also have large extracellular domains that facilitate particle alignments in the determination of high resolution structures. Multiple class C receptors have been studied using cryo-EM; γ-aminobutyric acid receptors (GABA B ), − multiple metabotropic glutamate receptors (mGlu), − and the calcium sensing receptor (CaS) . The structures of these receptors were solved in the presence of a variety of ligands, including agonists, inverse agonists, and antagonists, facilitating the understanding of the structural changes that occur upon ligand binding and G protein binding, and for understanding how to target these receptors by different ligand classes.…”

Section: Notable Examples In Membrane Protein Cryo-em: Learning From ...mentioning

confidence: 99%

Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM

et al. 2022

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Membrane proteins are highly diverse in both structure and function and can, therefore, present different challenges for structure determination. They are biologically important for cells and organisms as gatekeepers for information and molecule transfer across membranes, but each class of membrane proteins can present unique obstacles to structure determination. Historically, many membrane protein structures have been investigated using highly engineered constructs or using larger fusion proteins to improve solubility and/or increase particle size. Other strategies included the deconstruction of the full-length protein to target smaller soluble domains. These manipulations were often required for crystal formation to support X-ray crystallography or to circumvent lower resolution due to high noise and dynamic motions of protein subdomains. However, recent revolutions in membrane protein biochemistry and cryo-electron microscopy now provide an opportunity to solve high resolution structures of both large, >1 megadalton (MDa), and small, <100 kDa (kDa), drug targets in near-native conditions, routinely reaching resolutions around or below 3 Å. This review provides insights into how the recent advances in membrane biology and biochemistry, as well as technical advances in cryoelectron microscopy, help us to solve structures of a large variety of membrane protein groups, from small receptors to large transporters and more complex machineries.

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“…This N-terminal tail is arranged as a Venus Flytrap Domain (VFTD) which forms the orthosteric binding site, where the endogenous ligand, glutamate, binds. The VFTD is connected to the 7TM by a cysteine-rich domain ( Nasrallah et al, 2021 ) ( Figure 1 ). In addition to binding to the orthosteric site, ligands can bind to sites that are topographically distinct from the orthosteric site, known as the allosteric site.…”

Section: The Type 5 Metabotropic Glutamate Receptormentioning

confidence: 99%

Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?

et al. 2022

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The type 5 metabotropic glutamate receptor, mGlu5, has been proposed as a potential therapeutic target for the treatment of several neurodegenerative diseases. In preclinical neurodegenerative disease models, novel allosteric modulators have been shown to improve cognitive performance and reduce disease-related pathology. A common pathological hallmark of neurodegenerative diseases is a chronic neuroinflammatory response, involving glial cells such as astrocytes and microglia. Since mGlu5 is expressed in astrocytes, targeting this receptor could provide a potential mechanism by which neuroinflammatory processes in neurodegenerative disease may be modulated. This review will discuss current evidence that highlights the potential of mGlu5 allosteric modulators to treat neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, this review will explore the role of mGlu5 in neuroinflammatory responses, and the potential for this G protein-coupled receptor to modulate neuroinflammation.

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Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations

Cited by 35 publications

References 69 publications

Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2

Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2

Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM

Targeting the Type 5 Metabotropic Glutamate Receptor: A Potential Therapeutic Strategy for Neurodegenerative Diseases?

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