Journal article
Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
JM Brouwer, P Lan, AD Cowan, JP Bernardini, RW Birkinshaw, MF van Delft, BE Sleebs, AY Robin, A Wardak, IK Tan, B Reljic, EF Lee, WD Fairlie, MJ Call, BJ Smith, G Dewson, G Lessene, PM Colman, PE Czabotar
Molecular Cell | CELL PRESS | Published : 2017
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. Brouwer et al. describe the first crystal structures of BH3-onl..
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Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
We thank Janet Newman and colleagues at the CSIRO C3 crystallization facility; Matthew Call for discussions; Jai Rautela, Mike Ryan, David Huang, David Segal, Sweta Iyer, and Michael Dengler for reagents and technical assistance; and Natasha Ritchie for proofreading the manuscript. This research was undertaken in part using the MX1 and MX2 crystallography beamlines at the Australian Synchrotron, Victoria, Australia, and made use of the ACRF Detector. P.E.C., G.L., and P.M.C. acknowledge NHMRC Fellowships (1079700, 1117089, 1116934). Our work is supported by NHMRC (Australia; Projects Grants 1079706 and 1059290 and Program Grant 1113133), the Australian Cancer Research Foundation, the Leukemia and Lymphoma Society (U.S.) (SCOR grant 7001-03), the Victorian State Government Operational Infrastructure Support, the Australian Government NHMRC IRIISS, and we acknowledge the support of the Walter and Eliza Hall Institute through the Catalyst Fund.