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Related Concept Videos

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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Transducer Mechanism: G Protein–Coupled Receptors01:30

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Conformational diversity in class C GPCR positive allosteric modulation.

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|January 13, 2025
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Summary
This summary is machine-generated.

Positive allosteric modulators (PAMs) alter metabotropic glutamate receptor 5 (mGlu5) function by binding to distinct sites, influencing receptor equilibrium and conformational changes. This reveals how PAMs modulate mGlu5 receptor activity for potential therapeutic applications.

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Area of Science:

  • Neuroscience
  • Structural Biology
  • Pharmacology

Background:

  • Metabotropic glutamate receptors (mGluRs) are class C G protein-coupled receptors crucial for neurotransmission.
  • mGluRs, like mGlu5, are activated by L-glutamate and possess a Venus Fly Trap (VFT) domain linked to a transmembrane domain (7TM).
  • Positive allosteric modulators (PAMs) target the 7TM domain to enhance mGluR signaling, offering therapeutic potential for neurological disorders.

Purpose of the Study:

  • To elucidate the structural mechanisms by which distinct PAMs modulate the metabotropic glutamate receptor 5 (mGlu5).
  • To understand how PAM binding influences the conformational landscape and functional states of the mGlu5 receptor.
  • To identify intermediate receptor states and their associated interactions.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structures of mGlu5 receptor complexes.
  • mGlu5 receptor was purified with three chemically and pharmacologically distinct PAMs.
  • Structural analysis focused on PAM binding modes and their impact on receptor conformation.

Main Results:

  • Cryo-EM structures revealed distinct binding modes for three different PAMs on the mGlu5 receptor.
  • PAMs were found to modulate the receptor equilibrium, shifting it towards the active state through their interactions within the 7TM domain.
  • A PAM-free, agonist-bound intermediate state was identified, highlighting interactions involving intracellular loop 2.

Conclusions:

  • PAMs allosterically modulate mGlu5 receptor activity by binding to the 7TM domain, influencing its conformational equilibrium.
  • The distinct binding modes of PAMs explain their varied effects on mGlu5 receptor function.
  • Understanding these structural and functional relationships is key for developing targeted therapeutics for neurological conditions.