Abstract

Cyclic peptides are emerging as a promising class of candidate drugs and biological probes due to their potential to achieve exceptional affinity and specificity for challenging targets, such as protein-protein interactions. To date, however, the molecular underpinnings of the interactions made by these peptides with their targets have not been systematically explored.
In this talk I will discuss use of the Random nonstandard Peptide Integrated Discovery (RaPID) platform to develop cyclic peptide inhibitors of multiple acetyllysine-binding bromodomains from the Bromodomain and ExtraTerminal domain (BET) family of epigenetic regulators. Structural analyses of multiple peptide-bromodomain complexes reveal highly diverse structures amongst the identified cyclic peptide ligands, including both alpha-helical and beta-sheet type structures, despite that fact that all of the peptides studied bind to the same acetyllysine binding pocket. These structures demonstrate for the first time that cyclic peptide ligands are capable of binding through multiple, entirely divergent modes to a single pocket, a finding with broader implications for peptide design and one which likely contributes to the success of library strategies for isolating high-affinity ligands.