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PDBsum entry 4bpi
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References listed in PDB file
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Key reference
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Title
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Structure-Guided rational design of α/β-Peptide foldamers with high affinity for bcl-2 family prosurvival proteins.
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Authors
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B.J.Smith,
E.F.Lee,
J.W.Checco,
M.Evangelista,
S.H.Gellman,
W.D.Fairlie.
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Ref.
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Chembiochem, 2013,
14,
1564-1572.
[DOI no: ]
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PubMed id
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Abstract
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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.
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