Abstract
Protein–protein interactions (PPI) play a crucial role in many biological processes and modulation of PPI using small molecules to target hot spots has therapeutic value. As a model system we will use PPI of human epidermal growth factor receptors (EGFRs). Among the four EGFRs, EGFR–HER2 and HER2–HER3 are well known in cancer. We have designed a small molecule that is targeted to modulate HER2-mediated signaling. Our approach is novel because the small molecule designed disrupts dimerization not only of EGFR–HER2, but also of HER2–HER3. In the present study we have shown, using surface plasmon resonance analysis, that a peptidomimetic, compound 5, binds specifically to HER2 protein extracellular domain and disrupts the dimerization of EGFRs. To evaluate the effect of compound 5 on HER2 signaling in vitro, Western blot and PathHunter assays were used. Results indicated that compound 5 inhibits the phosphorylation of HER2 kinase domain and inhibits the heterodimerization in a dose-dependent manner. Molecular modeling methods were used to model the PPI of HER2–HER3 heterodimer.
Highlights
Protein-protein interactions (PPI) play a crucial role in many biological processes, including transmembrane signal transduction, cell regulation, and the immune response (Wells & McClenden, 2007; Reichmann et al, 2007)
HER2, epidermal growth factor receptors (EGFRs), HER3, and domain IV of HER2 were injected onto the chip surface at a rate of 10 μL/min until response units of approximately 7000 RU were reached
A stable surface of the immobilized proteins 7500 RU for HER2-extracellular domain (ECD), 9000 RU for HER3-ECD, 7000 RU for EGFR-ECD, and 11,000 RU for domain IV-HER2 were obtained after injection
Summary
Protein-protein interactions (PPI) play a crucial role in many biological processes, including transmembrane signal transduction, cell regulation, and the immune response (Wells & McClenden, 2007; Reichmann et al, 2007). Detailed studies of PPI interaction surfaces and the amino acid residues by several researchers have indicated that there are “hot spots” on the protein-protein interface area where major contributions to binding free energy are provided. These hot spots have core regions consisting mostly of aromatic amino acid residues such as Tyr, Trp, and Phe (Bahadur, Chakrabarti, Rodier & Janin, 2004; Moreira, Fernandes & Ramos, 2007; Chene, 2006). We will use PPI of human epidermal growth factor receptors (EGFRs)
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