Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies.

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.
Mesh Terms:
Amino Acid Sequence, Apoptosis, Binding Sites, Carrier Proteins, Humans, Models, Molecular, Mutagenesis, Site-Directed, Nuclear Magnetic Resonance, Biomolecular, Peptides, Protein Binding, Protein Engineering, Protein Structure, Secondary, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, Structure-Activity Relationship, bcl-Associated Death Protein, bcl-X Protein
Protein Sci.
Date: Dec. 01, 2000
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