Solution structure of a beta-peptide ligand for hDM2.
We recently reported a beta-peptide foldamer, beta53-1, 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 beta53-1 in methanol. Details of the structure illustrate fundamental and novel elements of beta-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 beta53-1 14-helix geometry alters the presentation of its recognition epitope, rendering it particularly well suited for alpha-helix mimicry. The solution structure of beta53-1 demonstrates that well folded beta-peptide oligomers can effectively present an extended, highly variable surface that could be used as a general platform for targeting critical protein-protein interfaces.
Kritzer
Joshua A
JA
Department of Chemistry, Yale University, New Haven, Connecticut 06510, USA.
Hodsdon
Michael E
ME
Schepartz
Alanna
A
D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012996:Solutions
D008024:Ligands; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D012996:Solutions; D051736:Proto-Oncogene Proteins c-mdm2