Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design

Mol Cell. 2017 Nov 16;68(4):659-672.e9. doi: 10.1016/j.molcel.2017.11.001.

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.

Keywords: Bak; Bcl-2 family; Bim; apoptosis; inhibitor; non-natural amino acid.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Bcl-2-Like Protein 11* / chemistry
  • Bcl-2-Like Protein 11* / pharmacology
  • Cell Line, Transformed
  • Humans
  • Mice
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Peptides* / chemistry
  • Peptides* / pharmacology
  • Protein Binding
  • Structure-Activity Relationship
  • bcl-2 Homologous Antagonist-Killer Protein* / chemistry
  • bcl-2 Homologous Antagonist-Killer Protein* / genetics
  • bcl-2 Homologous Antagonist-Killer Protein* / metabolism

Substances

  • BAK1 protein, human
  • Bak1 protein, mouse
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Peptides
  • bcl-2 Homologous Antagonist-Killer Protein