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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—loss of PPI function can disrupt a cellular process.

 

Prevention of protein–protein interaction function

PPI function of a specific PPID can be prevented by an appropriate short linear peptide (Figure 1).

 

tech peptide protein protein interaction inhibitors fig 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 (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 (PDB ID: 1YCR). (c) Tool bound to target—PPI function of a specific PPID can be prevented by an appropriate short linear peptide (PDB ID: 1YCR).

 

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 the 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.
tech peptide protein protein interaction inhibitors table 1
(1) If the fusion protein is expressed in transfected 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.

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