Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation

作者：Ottis Philipp; Toure Momar; Cromm Philipp M; Ko Eunhwa; Gustafson Jeffrey L; Crews Craig M^*

来源：ACS Chemical Biology, 2017, 12(10): 2570-2578.

DOI：10.1021/acschembio.7b00485

Proteolysis targeting chimera (PROTAC) technology, the recruitment of E3 ubiquitin ligases to induce the degradation of a protein target, is rapidly impacting chemical biology, as well as modern drug development. Here, we explore the universality Of this approach by evaluating different E3 ubiquitin ligases, engineered in their :substrate binding domains to accept a recruiting ligand. Five out of six E3 ligases were found to be amenable to recruitment for target degradation. Taking advantage of the tight spatiotemporal control of inducing ubiquitination on a preselected target in living cells, we focused on two of the engineered E3 ligases, beta TRCP and parkin, to unravel their ubiqUitination characteristics in comparison with the PROTAC-recruited endogenous E3 ligases VHL and cereblon.

• 出版日期2017-10