Back to Search
Start Over
Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction.
- Source :
-
Chembiochem : a European journal of chemical biology [Chembiochem] 2006 Mar; Vol. 7 (3), pp. 515-26. - Publication Year :
- 2006
-
Abstract
- Inhibitors of the interaction between the p53 tumor-suppressor protein and its natural human inhibitor HDM2 are attractive as potential anticancer agents. In earlier work we explored designing beta-hairpin peptidomimetics of the alpha-helical epitope on p53 that would bind tightly to the p53-binding site on HDM2. The beta-hairpin is used as a scaffold to display energetically hot residues in an optimal array for interaction with HDM2. The initial lead beta-hairpin mimetic, with a weak inhibitory activity (IC(50)=125 microM), was optimized to afford cyclo-(L-Pro-Phe-Glu-6ClTrp-Leu-Asp-Trp-Glu-Phe-D-Pro) (where 6ClTrp=L-6-chlorotryptophan), which has an affinity almost 1,000 times higher (IC(50)=140 nM). In this work, insights into the origins of this affinity maturation based on structure-activity studies and an X-ray crystal structure of the inhibitor/HDM2(residues 17-125) complex at 1.4 A resolution are described. The crystal structure confirms the beta-hairpin conformation of the bound ligand, and also reveals that a significant component of the affinity increase arises through new aromatic/aromatic stacking interactions between side chains around the hairpin and groups on the surface of HDM2.
- Subjects :
- Amino Acid Sequence
Crystallization
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular
Protein Binding
Protein Conformation
Structure-Activity Relationship
Epitopes chemistry
Epitopes immunology
Molecular Mimicry
Proto-Oncogene Proteins c-mdm2 chemistry
Tumor Suppressor Protein p53 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1439-4227
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Chembiochem : a European journal of chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 16511824
- Full Text :
- https://doi.org/10.1002/cbic.200500452