Direct and Selective Small-molecule Activation of Proapoptotic BAX

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2012 May 29

PMID 22634637

Citations 78

Authors

Evripidis Gavathiotis

Denis E Reyna

Joseph A Bellairs

Elizaveta S Leshchiner

Loren D Walensky

Affiliations

Soon will be listed here.

Abstract

BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis.

Citing Articles

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