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Allosteric sensitization of proapoptotic BAX

Jonathan R Pritz1, Franziska Wachter1, Susan Lee1

  • 1Department of Pediatric Oncology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

Nature Chemical Biology
|July 11, 2017
PubMed

Insights

Researchers identified a novel compound that modulates BCL-2-associated X protein (BAX) activity. This discovery offers a new therapeutic strategy by lowering the apoptotic threshold, addressing challenges in BAX-targeted drug development.

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.

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