Solution structure of a β-peptide ligand for hDM2

We recently reported a β-peptide foldamer, β53-1, that folds into a 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and potently inhibits the interaction of hDM2 with a peptide derived from the activation domain of p53 (p53AD). Here, we present the solution structure of β53-1 in methanol. Details of the structure illustrate fundamental and novel elements of β-peptide folding and recognition. These elements include the detailed arrangement of a complex, 14-helix-stabilizing salt bridge on one helical face, and a unique "wedge into cleft" packing interaction along a second. The structure also reveals how a subtle distortion in the β53-1 14-helix geometry alters the presentation of its recognition epitope, rendering it particularly well suited for α-helix mimicry. The solution structure of β53-1 demonstrates that well folded β-peptide oligomers can effectively present an extended, highly variable surface that could be used as a general platform for targeting critical protein-protein interfaces. Copyright © 2005 American Chemical Society.