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Harnessing FBXO31 with terminal amide-functionalized molecules for targeted protein degradation

ABSTRACT: 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 rapid and potent target degradation. Mechanistic studies confirm FBXO31-mediated ternary complex formation and identify key residues in FBXO31 required for recruiter engagement and target degradation. We further show that an FBXO31-based multi-kinase degrader exhibits a distinct and broader degradation profile than a CRBN-based degrader, highlighting a potentially expanded degradable target space beyond CRBN.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Xiaoyu Zhang

LAB HEAD: Xiaoyu Zhang

PROVIDER: PXD073606 | Pride | 2026-04-09

REPOSITORIES: pride

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			Action	DRS
	293T_FBXO31_APMS_MS3_16plex.raw	Raw
	293T_FBXO31_APMS_RTS_16plex.raw	Raw
	293T_FBXO31_F1_WP_RTS_10plex_01.raw	Raw
	293T_FBXO31_F1_WP_RTS_10plex_02.raw	Raw
	293T_FBXO31_F1_WP_RTS_10plex_03.raw	Raw

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