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Monitoring On-Target Signaling Responses in Larval Zebrafish - Z-REX Unmasks Precise Mechanisms of Electrophilic Drugs and Metabolites
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Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism

Yuta Horie1,2, Takafumi Suzuki1, Jin Inoue3,4

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.

Communications Biology
|May 15, 2021
PubMed

Insights

The Keap1-Nrf2 pathway regulates cellular defense against stress. This study reveals a Hinge-Latch mechanism for Nrf2 activation by non-electrophilic inhibitors, crucial for developing new drugs.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Pharmacology

Background:

  • The Keap1-Nrf2 system is vital for mammalian cytoprotection and a key drug target.
  • The Hinge-Latch model describes Nrf2 activation via specific motif interactions with Keap1.
  • Simultaneous analysis of these interactions has been technically challenging.

Purpose of the Study:

  • To investigate the dynamics of Keap1-Nrf2 motif interactions during activation.
  • To elucidate the mechanism of Nrf2 activation by different types of stimuli.
  • To provide insights for developing novel Keap1-Nrf2 pathway modulators.

Main Methods:

  • Utilized Nuclear Magnetic Resonance (NMR) spectroscopy titration experiments.
  • Analyzed protein-protein interactions (PPIs) between Keap1 and Nrf2 motifs.
  • Examined the effect of low-molecular-weight inhibitors and electrophilic inducers.

Main Results:

  • NMR experiments revealed the distinct binding status of Keap1-Nrf2 motifs.
  • Latch dissociation was triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors.
  • Latch dissociation occurred during p62-mediated Nrf2 activation but not with electrophilic inducers.

Conclusions:

  • Keap1 employs a Hinge-Latch mechanism for Nrf2 activation by non-electrophilic PPI inhibitors.
  • This mechanism is distinct from activation by electrophilic Nrf2 inducers.
  • Findings are critical for designing next-generation Nrf2 activators targeting Keap1-Nrf2 PPI.

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