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Single-Molecule Biosensing by Fluorescence Resonance Energy Transfer
Published in Shuo Huang, Single-Molecule Tools for Bioanalysis, 2022
SmFRET has also been applied to studies of the conformational dynamics of activation of G-protein-coupled receptors (GPCR) which constitute the largest family of membrane receptors in eukaryotes. Metabotropic glutamate receptors (mGluR) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity and are drug targets for neurological disorders [117]. By smFRET, Vafabakhsh et al. probed the activation of full-length mammalian group II mGluR2 (Figure 3.8c) [42] and showed that the ligand-binding domains interconvert between three conformations: a resting, an activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states with efficacy determined by occupancy of the active conformation. Their results supported a general mechanism for the activation of mGluRs in which agonist binding induces closure of the ligand-binding domains, followed by reorientation of the dimeric interface.
Receptors 2
Published in James E. Ferrell, Systems Biology of Cell Signaling, 2021
In Chapter 2 we examined the binding of a monomeric ligand to a monomeric receptor, a type of interaction that is commonplace in cell signaling. But multimeric receptors and ligands are common as well. Some G-protein-coupled receptors, such as the metabotropic glutamate receptor, function as dimers rather than monomers. Many receptor tyrosine kinases are multimeric and some of their ligands are as well. For example, the well-studied epidermal growth factor receptor (EGFR) is thought to function as a dimer in which two epidermal growth factor (EGF) molecules interact with two receptor molecules to yield an active EGF2–EGFR2 complex. The platelet-derived growth factor (PDGF) receptor is dimeric too, and it binds a PDGF dimer. The downstream Raf proteins also function as dimers, as do many of the further downstream transcription factors. Dimerization is not peculiar to receptor tyrosine kinase signaling—it has been estimated that, all told, perhaps 35% of proteins form homodimers, trimers, or larger polymeric complexes (Figure 3.1).
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
As in other cases, allosteric drugs may be classified as covalent (see below) or noncovalent. To the latter belong the benzodiazepines, the non-benzodiazepine Z-drugs (zopiclone, zolpidem, etc.) or barbiturate drugs, targeting the ionotropic GABA receptor and acting as positive allosteric modulator molecules that increase the activity of the GABAA receptor protein in the central nervous system (e.g., Henschel et al., 2008). Cinacalcet is a positive G-protein-coupled receptor (GPCR) modulator that enhances Ca2+ activation of calcium-sensing receptor (Brown, 2010) and is employed to treat hyperparathyroidism; the cellular mechanisms for allosteric modulation of calcium-sensing receptors has been discussed by Cavanaugh et al. (2012). Maraviroc is a negative modulator of the GPCR chemokine receptor CCR5 and used for the treatment of HIV-type 1 (Conn et al., 2009, and literature cited therein). Metabotropic glutamate receptors (mGluRs, several different groups) involved in the modulation of synaptic transmission and neuronal excitability are members of the GPCR superfamily; mGluRs are drug targets of positive allosteric modulators for treating neurological and psychiatric disorders (Alzheimer’s, anxiety, schizophrenia, etc.) as reviewed by Niswender and Conn (2010), Wood et al. (2011), or Herman et al. (2012). A recent example are allosteric BCR-ABL tyrosine kinase fusion protein inhibitors in Philadelphia chromosome-positive acute lymphoblastic leukemia, developed to overcome resistance towards drugs like imatinib and others (Hantschel, 2012). For covalent allosteric inhibitors see the next section.
Intra-carotid body inter-cellular communication
Published in Journal of the Royal Society of New Zealand, 2023
Liam P. Argent, Aabharika Bose, Julian F. R. Paton
Similar to ATP, glutamate also has inhibitory as well as excitatory effects on the carotid body. It has recently been reported that the metabotropic glutamate receptor mGluR1 is expressed in type I cells (Li et al. 2021). The activation of this receptor by a selective agonist was shown to inhibit hypoxia-driven chemotransmission (Li et al. 2021).