Allosteric sensitization of proapoptotic BAX
| Autor: | Gregory J. Heffron, Jonathan R. Pritz, John R. Engen, Thomas E. Wales, Daniel T. Cohen, Susan Lee, Franziska Wachter, Walter Massefski, James Luccarelli, Paul Coote, Loren D. Walensky |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Programmed cell death Magnetic Resonance Spectroscopy Allosteric regulation Regulator Apoptosis Plasma protein binding Article 03 medical and health sciences Drug Delivery Systems Humans Molecular Biology bcl-2-Associated X Protein 030102 biochemistry & molecular biology Dose-Response Relationship Drug Chemistry Phenyl Ethers Bcl-2 family Cell Biology Small molecule Cell biology Cytosol 030104 developmental biology Membrane protein Proto-Oncogene Proteins c-bcl-2 Protein Binding |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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