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Published on: November 9, 2020
Harnessing FBXO31 with Terminal Amide-Functionalized Molecules for Targeted Protein Degradation
Chenlu Zhang1, Xiaokang Jin1, Chen Zhou1
1Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
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Targeted protein degradation (TPD) is a powerful strategy for controlling protein abundance. Here, we establish FBXO31 as a TPD-competent E3 ligase by exploiting its recognition of C-terminal amide-bearing degrons. Using an amidated Ala-Phe motif as a chemical recruiter, multiple small-molecule binders can be transformed into FBXO31-dependent degraders that induce the rapid and potent degradation of FKBP12, multiple kinases, and BET proteins BRD2, BRD3, and BRD4. Mechanistic studies confirm FBXO31-mediated ternary complex formation and identify key residues in FBXO31 required for recruiter engagement and target degradation.
