Conversion of Bim-BH3 from activator to inhibitor of Bak through structure-based design
- Author(s)
- Brouwer, JM; Lan, P; Cowan, AD; Bernardini, JP; Birkinshaw, RW; van Delft, MF; Sleebs, BE; Robin, AY; Wardak, A; Tan, IK; Reljic, B; Lee, EF; Fairlie, WD; Call, MJ; Smith, BJ; Dewson, G; Lessene, G; Colman, PM; Czabotar, PE;
- Details
- Publication Year 2017-11-16,Volume 68,Issue #4,Page 659-672 e9
- Journal Title
- Molecular Cell
- Publication Type
- Journal Article
- 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.
- Publisher
- Cell Press
- Research Division(s)
- Structural Biology; Cell Signalling And Cell Death; Chemical Biology
- PubMed ID
- 29149594
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2017.11.001
- NHMRC Grants
- NHMRC/1079700, NHMRC/1117089, NHMRC/1116934, NHMRC/1079706, NHMRC/1059290, NHMRC/1113133,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-11-29 08:58:25
Last Modified: 2017-12-11 04:27:03