Chemically targeting the redox switch in AP1 transcription factor ΔFOSB

Area of Science:

• Neuroscience
• Structural Biology
• Pharmacology

Background:

• The AP1 transcription factor delta FosB (ΔFOSB) accumulates in the brain following chronic insults, mediating long-term neuroadaptations.
• ΔFOSB forms heterodimers with other AP1 factors, like JUND, regulated by a cysteine-based redox switch controlling DNA binding.

Purpose of the Study:

• To elucidate the structural basis of the ΔFOSB/JUND redox switch.
• To identify and characterize compounds targeting this redox switch for potential therapeutic applications.

Main Methods:

• Determined the crystal structure of ΔFOSB/JUND bZIP domains in their reduced, DNA-free state.
• Screened a library of 3200 thiol-reactive compounds to identify redox switch inhibitors.
• Validated compound activity biochemically and in cell-based assays.
• Determined the crystal structure of the complex between ΔFOSB/JUND bZIP domains and a targeting compound.

Main Results:

• Revealed the structural basis of the redox switch mechanism.
• Identified specific compounds that target the ΔFOSB/JUND redox switch.
• Demonstrated that these compounds are well-tolerated in cell lines.
• Discovered a deep compound-binding pocket near the DNA-binding site in the ΔFOSB/JUND complex.

Conclusions:

• ΔFOSB and related AP1 transcription factors can be specifically targeted by exploiting their unique redox switch.
• This provides a novel strategy for modulating the biological function of previously considered undruggable proteins.
• Offers potential for developing new therapeutics for conditions associated with ΔFOSB accumulation.