Allosteric sensitization of proapoptotic BAX.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• BCL-2-associated X protein (BAX) is a key regulator of apoptosis.
• BAX transitions from a cytosolic monomer to a mitochondrial oligomer.
• Developing drugs targeting BAX is challenging due to its aggregation-prone nature.

Purpose of the Study:

• To overcome challenges in screening BAX and identify modulators.
• To understand the mechanism of BAX activation and oligomerization.
• To explore therapeutic strategies for modulating BAX activity.

Main Methods:

• Performed an NMR-based fragment screen of full-length human BAX.
• Conducted biochemical and structural analyses of identified compounds.
• Investigated the allosteric effects of the compound on BAX conformation.

Main Results:

• Identified a compound that sensitizes BAX activation.
• The compound binds to a pocket at the junction of α3-α4 and α5-α6 hairpins.
• The compound allosterically mobilizes the α1-α2 loop and BAX BH3 helix, key to BAX activation and oligomerization.

Conclusions:

• The identified compound reveals fundamental mechanisms of BAX conformational regulation.
• The compound engages hydrophobic interactions preserving the inactive BAX state.
• This provides a new opportunity to reduce the apoptotic threshold for therapeutic benefit.