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. 2000 Dec;9(12):2528–2534. doi: 10.1110/ps.9.12.2528

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

A M Petros 1, D G Nettesheim 1, Y Wang 1, E T Olejniczak 1, R P Meadows 1, J Mack 1, K Swift 1, E D Matayoshi 1, H Zhang 1, C B Thompson 1, S W Fesik 1
PMCID: PMC2144516  PMID: 11206074

Abstract

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.

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Selected References

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