Two former PhD students in the Mott-Owen Group have published a paper in Biochemistry based on their doctoral research. Natasha Murphy and George Tetley collaborated with Jefferson Revell at AstraZeneca to report their engineering of a new generation of disulfide-cyclized peptide inhibitors that target Cdc42 by mimicking the binding mode of its native effector proteins.
The structure revealed the striking result that the peptide adopts an ordered beta-hairpin conformation and docks against the beta-2 strand of the GTPase Rossmann fold, forming a short antiparallel beta-sheet that extends the protein's own secondary structure. The work demonstrates that the flat, seemingly undruggable effector-binding surfaces of small GTPases can be selectively targeted by constrained peptides that recreate natural protein-protein interactions.
Tasha has just rejoined the Department as a postdoc with Jenny Molloy.
Read the paper: Cyclized Peptide Inhibitors of the Small G Protein Cdc42 Mimic Binding of Effector Proteins
Read a discussion on the American Peptide Society website