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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
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Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
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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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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
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Related Experiment Video

Updated: Jun 23, 2025

Monitoring On-Target Signaling Responses in Larval Zebrafish - Z-REX Unmasks Precise Mechanisms of Electrophilic Drugs and Metabolites
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A double whammy for KEAP1.

Jan Gerhartz1, Radosław P Nowak1

  • 1Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany.

Cell Chemical Biology
|June 21, 2024
PubMed
Summary

Researchers discovered a bivalent KEAP1 inhibitor (biKEAP1) that quickly activates NRF2. This new compound effectively suppresses acute inflammation in animal models, offering a promising therapeutic avenue.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • The KEAP1-NRF2 pathway is a critical regulator of cellular defense against oxidative stress.
  • Dysregulation of this pathway is implicated in various diseases, including cancer and inflammatory conditions.
  • Monovalent KEAP1 inhibitors have shown potential but exhibit limitations in activation speed.

Purpose of the Study:

  • To discover and characterize novel inhibitors of KEAP1.
  • To evaluate the efficacy of a newly identified bivalent KEAP1 inhibitor (biKEAP1) in activating NRF2.
  • To assess the anti-inflammatory effects of biKEAP1 in preclinical models.

Main Methods:

  • Chemical synthesis and characterization of bivalent KEAP1 inhibitors.
  • Biochemical assays to measure NRF2 activation.

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  • In vivo studies using animal models of acute inflammation.

    • Main Results:

    • Discovery of biKEAP1, a potent bivalent inhibitor of KEAP1.
    • biKEAP1 demonstrates more rapid activation of NRF2 compared to monovalent inhibitors.
    • biKEAP1 effectively suppresses acute inflammation in animal models.

    Conclusions:

    • Bivalent KEAP1 inhibition represents a promising strategy for enhanced NRF2 activation.
    • biKEAP1 shows therapeutic potential for treating inflammatory diseases.
    • Further investigation into biKEAP1 as a drug candidate is warranted.