3 years ago

Allosteric sensitization of proapoptotic BAX

Allosteric sensitization of proapoptotic BAX
Paul Coote, Daniel T Cohen, Franziska Wachter, Walter Massefski, John R Engen, Gregory J Heffron, Thomas E Wales, James Luccarelli, Jonathan R Pritz, Loren D Walensky, Susan Lee
BCL-2-associated X protein (BAX) is a critical apoptotic regulator that can be transformed from a cytosolic monomer into a lethal mitochondrial oligomer, yet drug strategies to modulate it are underdeveloped due to longstanding difficulties in conducting screens on this aggregation-prone protein. Here, we overcame prior challenges and performed an NMR-based fragment screen of full-length human BAX. We identified a compound that sensitizes BAX activation by binding to a pocket formed by the junction of the α3–α4 and α5–α6 hairpins. Biochemical and structural analyses revealed that the molecule sensitizes BAX by allosterically mobilizing the α1–α2 loop and BAX BH3 helix, two motifs implicated in the activation and oligomerization of BAX, respectively. By engaging a region of core hydrophobic interactions that otherwise preserve the BAX inactive state, the identified compound reveals fundamental mechanisms for conformational regulation of BAX and provides a new opportunity to reduce the apoptotic threshold for potential therapeutic benefit.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2433

DOI: 10.1038/nchembio.2433

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