ABSTRACT
Minimal mimics of protein conformations provide rationally designed ligands to modulate protein function. The advantage of minimal mimics is that they can be chemically synthesized and coaxed to be proteolytically resistant; a key disadvantage is that minimization of the protein binding epitope may be associated with loss of affinity and specificity. Several approaches to overcome this challenge may be envisioned, including deployment of covalent warheads and use of nonnatural residues to improve contacts with the binding surface. Herein, we describe our computational and experimental efforts to enhance the minimal protein mimics with fragments that can contact undiscovered binding pockets on Mdm2 and MdmX-two well-studied protein partners of p53.
Subject(s)
Cell Cycle Proteins/metabolism , Peptides/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins/metabolism , Binding Sites , Cell Cycle Proteins/chemistry , Humans , Ligands , Molecular Docking Simulation , Peptides/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins c-mdm2/chemistryABSTRACT
The coiled coil is a common protein tertiary structure intimately involved in mediating protein recognition and function. Due to their structural simplicity, coiled coils have served as attractive scaffolds for the development of functional biomaterials. Herein we describe the design of conformationally-defined coiled coil photoswitches as potential environmentally-sensitive biomaterials.
