Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.
- Author(s)
- Smith, BJ; Lee, EF; Checco, JW; Evangelista, M; Gellman, SH; Fairlie, WD;
- Details
- Publication Year 2013-09-02,Volume 14,Issue #13,Page 1564-1572
- Journal Title
- Chembiochem : a European Journal of Chemical Biology
- Publication Type
- Journal Article
- Abstract
- We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three α residues of the original α/β backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new α/β-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.
- Publisher
- WILEY
- Keywords
- apoptosis ; BH3 domain ; Mcl-1; peptide design ; peptidomimetics
- Research Division(s)
- Structural Biology
- Link To PubMed Central Version
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970217/
- Publisher's Version
- https://doi.org/10.1002/cbic.201300351
- NHMRC Grants
- NHMRC/1041936, NHMRC/1008329,
- Terms of Use/Rights Notice
- Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Creation Date: 2013-09-02 12:00:00