期刊
CHEMBIOCHEM
卷 14, 期 13, 页码 1564-1572出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300351
关键词
apoptosis; BH3 domain; Mcl-1; peptide design; peptidomimetics
资金
- Australian Research Council [DP1093909]
- NHMRC of Australia [1041936, 1008329]
- NHMRC IRIISS [361646]
- Victorian State Government OIS
- NIH [GM056414, T32 GM008349]
- Australian Research Council [DP1093909] Funding Source: Australian Research Council
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.
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