Researchers in Bobby Arora's and Yingkai Zhang's groups collaborated on a study featured on the cover of JACS: "Targeting Unoccupied Surfaces on Protein-Protein Interfaces" (click here to read the full article).
Synopsis: Protein mimicry offers an effective strategy for modulating the effects of proteins involved in disease by blocking their harmful interactions with other proteins. A key challenge with direct mimicry of protein surfaces is that short segments often do not retain the binding affinity of the full-length protein. In an effort to overcome this general limitation, the Arora and Zhang Groups sought to incorporate non-natural residues to compensate for the missing contacts (DOI: 10.1021/jacs.7b05960). The effort was led by David Rooklin and Haotian Li in the Zhang Group, and Ashley Modell and Viktoriya Berdan in the Arora Lab.
The team focused on ligands for KIX, whose interactions with oncogenic transcription factors have been linked with leukemia. KIX uses a helix-strand motif to interact with its natural binding partner, MLL, but the researchers’ attempt of simply using a truncated helix did not replicate the binding. To obtain a more effective peptide, the researchers computationally mapped the binding interface between KIX and MLL to identify both targetable and underutilized sub-pocket space. Judicious substitution of residues in the truncated helix led to a peptide with affinity close to that of the wild type MLL. Inhibition of the KIX-MLL interaction has been proposed in the treatment of leukemia, so this study could influence the development of therapies in this area, and advance peptidomimetic design in general.
About the Cover: The cover illustrates application of a fragment-centric topographical mapping algorithm, termed AlphaSpace, to reveal underutilized subpocket space in protein–protein complexes as a guide for the incorporation of noncanonical residues into inhibitors. The noncanonical residues designed to optimize binding interactions are shown in magenta.
This work was supported by the National Institutes of Health.