Oral Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Converting an activator of apoptosis into an inhibitor through structure-based design (#30)

Jason M Brouwer 1 2 , Ping Lan 1 2 , Angus D Cowan 1 2 , Jonathan P Bernardini 1 2 , Richard W Birkinshaw 1 2 , Mark F van Delft 1 2 , Brad E Sleebs 1 2 , Adeline Y Robin 1 2 , Ahmad Wardak 1 , Iris K Tan 1 , Boris Reljic 1 2 , Erinna F Lee 3 4 5 , W. Douglas Fairlie 3 4 5 , Melissa J Call 1 2 , Brian J Smith 3 , Grant Dewson 1 2 , Guillaume Lessene 1 2 6 , Peter M Colman 1 2 , Peter E Czabotar 1 2
  1. Walter and Eliza Hall Institute, Parkville, VIC , Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  3. La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, Melbourne, Victoria, Australia
  4. Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia
  5. School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
  6. Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia

Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating conformational changes that lead to oligomerisation and result in permeabilisation of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis [1, 2]. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak [3]. These revealed a central cavity which may promote critical conformational changes upon activator BH3 binding. Peptides possessing non-natural amino acids were designed that fill this cavity and promote stability of the complex. These peptides stabilised Bak and inhibited its membrane permeabilisation activity [3]. These are the first structure based inhibitors of Bak or Bax and provide a molecular rationale for developing inhibitors of cell death for conditions in which excessive apoptosis is implicated such as ischemic reperfusion injury, hearing loss and acute stress related injuries.

  1. [1] Czabotar, et al., 2013. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell, 152, 519-31.
  2. [2] Brouwer, et al., 2014. Bak Core and Latch Domains Separate during Activation, and Freed Core Domains Form Symmetric Homodimers. Mol Cell, 55, 938-46.
  3. [3] Brouwer, et al., 2017. Conversion of Bim-BH3 from activator to inhibitor of Bak through structure-based design. Mol Cell, In Press