期刊
NATURE CHEMICAL BIOLOGY
卷 13, 期 9, 页码 961-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2433
关键词
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资金
- NIH [1R35CA197583, R01GM101135, F31CA189651, T32GM007753]
- Leukemia and Lymphoma Society (LLS) Scholar Award
- Todd J. Schwartz Memorial Fund
- Wolpoff Family Foundation
- William Lawrence and Blanche Hughes Foundation
- Alexander von Humboldt Foundation Feodor Lynen Fellowship
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 alpha 3-alpha 4 and alpha 5-alpha 6 hairpins. Biochemical and structural analyses revealed that the molecule sensitizes BAX by allosterically mobilizing the alpha 1-alpha 2 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.
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