Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.
Petros AM,
Nettesheim DG,
Wang Y,
Olejniczak ET,
Meadows RP,
Mack J,
Swift K,
Matayoshi ED,
Zhang H,
Thompson CB,
Fesik SW.
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA.
The three-dimensional structure of the anti-apoptotic protein Bcl-xL complexed to a 25-residue peptide from the death promoting region of Bad was determined using NMR spectroscopy. Although the overall structure is similar to Bcl-xL bound to a 16-residue peptide from the Bak protein (Sattler et al., 1997), the Bad peptide forms additional interactions with Bcl-xL. However, based upon site-directed mutagenesis experiments, these additional contacts do not account for the increased affinity of the Bad 25-mer for Bcl-xL compared to the Bad 16-mer. Rather, the increased helix propensity of the Bad 25-mer is primarily responsible for its greater affinity for Bcl-xL. Based on this observation, a pair of 16-residue peptides were designed and synthesized that were predicted to have a high helix propensity while maintaining the interactions important for complexation with Bcl-xL. Both peptides showed an increase in helix propensity compared to the wild-type and exhibited an enhanced affinity for Bcl-xL.
PMID: 11206074 [PubMed - indexed for MEDLINE]
PMCID: PMC2144516