Peptide protein–protein interaction inhibitors
A short linear peptide that matches (a part of) a specific protein–protein interaction domain (PPID) can be used as a tool that binds to a corresponding interacting / complementary PPID of an endogenous protein when added to cells in culture. As a consequence of that binding, protein–protein interaction (PPI) function of the targeted PPID will be prevented specifically, and as a consequence of that prevention, the targeted cellular process of interest can be disrupted. ♦♦♦ See also the above slideshow. ♦♦♦
Prevention of protein–protein interaction function
PPI function of a specific PPID can be prevented by an appropriate short linear peptide (Figure 1).
|Figure 1. Protein–protein interaction (PPI) function of a protein–protein interaction domain (PPID) prevented specifically. (a) Target—a representation of the tertiary structure of a PPID of MDM2 protein that has strong protein–protein interaction activity towards a PPID of p53 protein (freely interpreted from PDB ID: 1YCR). (b) Tool—a PPID-fragment (short linear peptide) of p53 protein that has strong PPI activity towards a PPID of MDM2 protein (freely interpreted from PDB ID: 1YCR). (c) Tool bound to target—PPI function of a specific PPID can be prevented by an appropriate short linear peptide (freely interpreted from PDB ID: 1YCR). Note: the representations of the protein structures were made with VMD (http://www.ks.uiuc.edu/Research/vmd/).|
Protein–protein interaction inhibition of a PPI of interest
Primary structure information that is generated in a PPID mapping research project can directly be used to derive peptide protein–protein interaction inhibitor candidates. For example, suppose Protein_X(1-500) binds to Protein_Y(1-600) and PPID mapping research revealed that Protein_X(1-500) seems to be able to bind to Protein_Y(226-244)—see also the Mapping protein–protein interaction domains section on our Yeast two-hybrid (Y2H) system page. Then it may be possible to block endogenous Protein_X–Protein_Y interaction in cells in culture with a linear peptide that matches PPID Protein_Y(226-244) or a part thereof (Table 1, in this case the peptide is fused to GFP-linker). See also our Development of protein–protein interaction inhibitor candidates web page.
|Table 1. Plasmids that encode GFP-linker-peptide, all possible 13- to 19-residue peptides that can be derived from Protein_Y(226-244) are covered.|
|(1) If the fusion protein is expressed in cells, then the Protein_Y-part of the fusion protein may bind to the targeted Protein_Y-binding protein–protein interaction domain (PPID) of endogenous Protein_X and cause loss of protein–protein interaction (PPI) function of the targeted PPID.|