Design strategies for the sequence-based mimicry of side-chain display in protein β-sheets by α/β-peptides
The sophistication of folding patterns and functions displayed by unnatural-backbone oligomers has increased tremendously in recent years. Design strategies for the mimicry of tertiary structures seem within reach; however, a general method for the mimicry of sheet segments in the context of a folded protein is an unmet need preventing realization of this goal. Previous work has shown that 1→1 α→β-residue substitutions at cross-strand positions in a hairpin-forming α-peptide sequence can generate an α/β-peptide analogue that folds in aqueous conditions but with a change in side-chain display relative to the natural sequence; this change would prevent application of single β-residue substitutions in a larger protein. Here, we evaluate four different substitution strategies based on replacement of αα dipeptide segments for the ability to retain both sheet folding encoded by a parent α-peptide sequence as well as nativelike side-chain display in the vicinity of the β-residue insertion point. High-resolution structure determination and thermodynamic analysis of folding by multidimensional NMR suggest that three of the four designs examined are applicable to larger proteins.
Lengyel, George A.,Horne, W. Seth
supporting information
p. 15906 - 15913,8
(2020/08/24)
Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding
Isothermal titration calorimetry and X-ray crystallography have been used to determine the structural and thermodynamic consequences associated with constraining the pTyr residue of the pYEEI ligand for the Src Homology 2 domain of the Src kinase (Src SH2
Davidson, James P.,Lubman, Olga,Rose, Thierry,Waksman, Gabriel,Martin, Stephen F.
p. 205 - 215
(2007/10/03)
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