Putting phage to work in deubiquitinase ligand discovery

Julie A Maupin-Furlow

doi:10.1074/jbc.h118.006803

Abstract

Inhibiting deubiquitinase (DUB) function is a promising strategy for the treatment of cancers and other human diseases. Of the hundreds of human DUBs, USP11 has emerged as an ideal therapeutic target, as it regulates DNA double-strand break repair by homologous recombination (HR) and other functions central to eukaryotic cell survival. A new study by Spiliotopoulos et al. cleverly uses next-generation phage display (NGPD) to identify peptide ligands that bind USP11 in a unique pocket that impacts HR. The study provides an important step toward novel DUB inhibitors that may reduce the resistance of some cancers to current treatment options.

Highlights

The ubiquitin-proteasome system (UPS)2 is an attractive target for the development of therapeutic agents, as it is needed for important processes in the human cell such as cell cycle progression and stress response
USP11 is involved in regulating DNA double-strand break repair by homologous recombination (HR) [1], but is putatively associated with several other pathways
The challenge is that USP11-specific interaction sites are not well defined, and no USP11-specific ligands exist

Summary

Introduction

The ubiquitin-proteasome system (UPS)2 is an attractive target for the development of therapeutic agents, as it is needed for important processes in the human cell such as cell cycle progression and stress response. To help resolve this issue, Dreveny and colleagues [5] use a new strategy to search for novel ligands that bind an accessory domain of USP11. This group had previously determined the X-ray crystal structure of the USP11 N-terminal domain and showed that this region had little impact on the isopeptidase activity of this DUB [6].

Results

Conclusion