1. Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
- Author
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Jason M. Brouwer, Ahmad Wardak, Grant Dewson, Mark F. van Delft, Adeline Y. Robin, Erinna F. Lee, Brad E. Sleebs, Iris K. L. Tan, Jonathan P. Bernardini, Peter M. Colman, W. Douglas Fairlie, Richard W Birkinshaw, Melissa J. Call, Brian J. Smith, Boris Reljic, Ping Lan, Guillaume Lessene, Peter E. Czabotar, and Angus D. Cowan
- Subjects
0301 basic medicine ,Programmed cell death ,Apoptosis ,Plasma protein binding ,Mitochondrion ,Biology ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Animals ,Humans ,Structure–activity relationship ,Molecular Biology ,Cell Line, Transformed ,Bcl-2-Like Protein 11 ,Activator (genetics) ,Bcl-2 family ,Cell Biology ,Mitochondria ,Cell biology ,bcl-2 Homologous Antagonist-Killer Protein ,030104 developmental biology ,biological phenomena, cell phenomena, and immunity ,Peptides ,Bacterial outer membrane ,Bcl-2 Homologous Antagonist-Killer Protein ,Protein Binding - Abstract
Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.
- Published
- 2017
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