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. 2010 Oct 18;11(15):2104-7.
doi: 10.1002/cbic.201000378.

High Specificity in Protein Recognition by Hydrogen-Bond-Surrogate α-Helices: Selective Inhibition of the p53/MDM2 Complex

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High Specificity in Protein Recognition by Hydrogen-Bond-Surrogate α-Helices: Selective Inhibition of the p53/MDM2 Complex

Laura K Henchey et al. Chembiochem. .
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Figures

Figure 1
Figure 1
(a) Hydrogen-bond-surrogate (HBS) α-helices feature a carbon–carbon bond in place of an i and i+4 hydrogen bond. R=amino acid side chain. (b) A short helical segment (dark gray) from the p53 activation domain targets Mdm2 with three hydrophobic residues Phe-19, Trp-23, and Leu-26 forming key contacts.
Figure 2
Figure 2
a) Circular dichroism spectra of 1, 4, 7, and 8 in 10% trifluoroethanol (TFE) in phosphate-buffered saline (PBS). b) Determination of peptide binding to His-tagged MDM2 by a fluorescence polarization assay. Circular dichroism spectra and fluorescence anisotropy binding curves for 2, 3, 5 and 6 are included in the Supporting Information.
Figure 3
Figure 3
Examples of helical protein interfaces evaluated in the current study: (a) p53 (dark gray)/MDM2 (light gray), (b) p53 (dark gray)/MDM4 (light gray), (c) Bak BH3 (dark gray)/Bcl-xL (light gray), and Hif-1α (dark gray)/CBP (light gray). PDB codes: 1YCR, 2DAB, 1BXL and (d) 1L8C.
Figure 4
Figure 4
Schematic for the cell-free interrogation of protein-protein interaction inhibitors. Reassembly of split-luciferase fusions of the interaction of interest results in luminescence. Inhibition of the protein complex formation results in abolishment of luciferase activity. Luciferase assays performed with 10 μM peptide, HBS helices and nutlin-3.
Scheme 1
Scheme 1
Placement of Phe-19 residue, from left to right, at the N-alkyl residue, inside and outside the HBS macrocycle.

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