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Structure-guided rational design of ?/?-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.


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 ?/?-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 ?/?-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 ? residues of the original ?/? 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 ?/?-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.

SUBMITTER: Smith BJ 

PROVIDER: S-EPMC3970217 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

Smith Brian J BJ   Lee Erinna F EF   Checco James W JW   Evangelista Marco M   Gellman Samuel H SH   Fairlie W Douglas WD  

Chembiochem : a European journal of chemical biology 20130808 13


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 modificat  ...[more]

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