Residue-based preorganization of BH3-derived alpha/beta-peptides: modulating affinity, selectivity and proteolytic susceptibility in alpha-helix mimics
- Author(s)
- Peterson-Kaufman, KJ; Haase, HS; Boersma, MD; Lee, EF; Fairlie, WD; Gellman, SH;
- Journal Title
- ACS Chem Biol
- Publication Type
- Journal Article in press
- Abstract
- We report progress toward a general strategy for mimicking the recognition properties of specific alpha-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both alpha- and beta-amino acid residues, with the density of the beta subunits low enough that an alpha-helix-like conformation can be adopted but high enough to interfere with protease activity. Previous studies with a different protein-recognition system that suggested ring-constrained beta residues can be superior to flexible beta residues in terms of maximizing alpha/beta-peptide affinity for a targeted protein surface. Here, we use mimicry of the 18-residue Bim BH3 domain to expand the scope of this strategy. Two significant advances have been achieved. First, we have developed and validated a new ring-constrained beta residue that bears an acidic side chain, which complements previously known analogues that are either hydrophobic or basic. Second, we have discovered that placing cyclic beta residues at sites that make direct contact with partner proteins can lead to substantial discrimination between structurally homologous binding partners, the proteins Bcl-xL and Mcl-1. Overall, this study helps to establish that alpha/beta-peptides containing ring-preorganized beta residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize alpha-helical partners.
- Publisher
- ACS
- Research Division(s)
- Structural Biology
- PubMed ID
- 25946900
- Publisher's Version
- https://doi.org/10.1021/acschembio.5b00109
- NHMRC Grants
- NHMRC/1041936, NHMRC/1024620,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-22 11:19:38
Last Modified: 2015-05-22 12:15:45