National Center for
5DX3: Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with Stapled Peptide SRC2-P3 and Estradiol
Stapled Peptides with gamma-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction
Angew. Chem. Int. Ed. Engl. (2016) 55 p.4252-4255
"Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the gamma-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor alpha. The best peptide (IC50 =89 nm) replaces isoleucine 689 with an S-gamma-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-gamma-methyl peptide minimizes the syn-pentane interactions between the alpha- and gamma-methyl groups.