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Title: Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
Austin Authors: Brouwer, Jason M;Lan, Ping;Cowan, Angus D;Birkinshaw, Richard W;van Delft, Mark F;Sleebs, Brad E;Robin, Adeline Y;Wardak, Ahmad;Tan, Iris K;Reljic, Boris;Lee, Erinna F;Fairlie, W Douglas;Call, Melissa J;Smith, Brian J;Dewson, Grant;Lessene, Guillaume;Colman, Peter M;Czabotar, Peter E
Affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia
La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Issue Date: 16-Nov-2017
Date: 2017-11-16
Publication information: Molecular Cell 2017; 68(4): 659-672
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.
DOI: 10.1016/j.molcel.2017.11.001
Journal: Molecular Cell
PubMed URL:
Type: Journal Article
Subjects: Bak
Bcl-2 family
non-natural amino acid
Appears in Collections:Journal articles

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