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Published on: October 9, 2016
Small-molecule allosteric inhibitors of BAX
Thomas P Garner1,2,3,4, Dulguun Amgalan2,3,4,5, Denis E Reyna1,2,3,4
1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
Abstract:
BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Upon binding by BH3-only proteins, cytosolic BAX undergoes conformational activation and translocation, resulting in mitochondrial outer-membrane permeabilization. Efforts to rationally target BAX and develop inhibitors have been elusive, despite the clear therapeutic potential of inhibiting BAX-mediated cell death in a host of diseases. Here, we describe a class of small-molecule BAX inhibitors, termed BAIs, that bind directly to a previously unrecognized pocket and allosterically inhibit BAX activation. BAI binding around the hydrophobic helix α5 using hydrophobic and hydrogen bonding interactions stabilizes key areas of the hydrophobic core. BAIs inhibit conformational events in BAX activation that prevent BAX mitochondrial translocation and oligomerization. Our data highlight a novel paradigm for effective and selective pharmacological targeting of BAX to enable rational development of inhibitors of BAX-mediated cell death.
Insights
Researchers discovered small-molecule BAX inhibitors (BAIs) that bind a novel pocket, allosterically inhibiting BAX activation. This finding offers a new strategy for developing drugs targeting BAX-mediated cell death in various diseases.
Area of Science:
- Molecular biology
- Biochemistry
- Pharmacology
Background:
- BAX protein is central to the mitochondrial cell death pathway.
- BAX activation leads to mitochondrial outer-membrane permeabilization, a key event in apoptosis.
- Targeting BAX for therapeutic inhibition has been challenging.
Purpose of the Study:
- To identify and characterize novel small-molecule inhibitors of BAX.
- To elucidate the mechanism of action for these BAX inhibitors.
- To establish a new paradigm for targeting BAX-mediated cell death.
Main Methods:
- Screening for small-molecule BAX inhibitors (BAIs).
- Biochemical assays to assess BAI binding and allosteric inhibition of BAX activation.
- Analysis of BAX conformational changes, mitochondrial translocation, and oligomerization.
Main Results:
- A novel class of small-molecule BAX inhibitors (BAIs) was identified.
- BAIs bind to a previously unrecognized pocket on BAX, stabilizing its hydrophobic core.
- BAI binding allosterically inhibits BAX activation, preventing mitochondrial translocation and oligomerization.
Conclusions:
- BAIs represent a novel class of BAX inhibitors with a unique allosteric mechanism.
- Targeting this newly identified pocket offers a promising strategy for developing BAX-specific therapeutics.
- This work provides a new paradigm for the rational development of inhibitors for BAX-mediated cell death.
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