Characterizing SHP2 as a Novel Therapeutic Target in Breast Cancer
Abstract
During this research period, molecular modeling and biochemical studies were conducted to assess the roles of different acidic residues in the binding of the Src homology 2-containing protein tyrosine phosphatase (SHP2) to its substrates. A peptide derived from this substrate was shown to be a selective inhibitor of SHP2. SHP1 was used as a control, and the peptide did not act on this enzyme. Molecular modeling revealed key binding determinants at the atomic level present in SHP2 that could not be recapitulated in SHP1. These modeling observations were tested using mutation of the peptide. Indeed, when the peptide was mutated to abolish these interactions, inhibitory capacity was abolished entirely. Systematic mutation of the peptide in silico further demonstrated that the substrate needed to bind both of the positively-charged amino acid sidechains adjacent to the active site to facilitate the highest binding stability. Mutation of any of the acidic amino acids next to the phosphotyrosine on the substrate produced significant defects in binding as predicted by molecular docking. These findings are now being parlayed into study of the peptide-based inhibitor on cells, which is work that will continue into the coming year.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2014
- Accession Number
- ADA610504
Entities
People
- Zachary C Hartman
Organizations
- West Virginia University