29hh
Cryo-EM structure of the CUL1-RBX1-SKP1-FBXO22 SCF ubiquition ligase in complex with NSD2, UNC10088 and Bach1
Structural highlights
FunctionFBX22_HUMAN Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Promotes the proteasome-dependent degradation of key sarcomeric proteins, such as alpha-actinin (ACTN2) and filamin-C (FLNC), essential for maintenance of normal contractile function.[1] Publication Abstract from PubMedTargeted protein degradation (TPD) through the ubiquitin-proteasome system is driven by compound-mediated polyubiquitination of a protein-of-interest by an E3 ubiquitin (Ub) ligase. Relatively few E3s have been successfully utilized for TPD and the governing principles of functional ternary complex formation between the E3, degrader, and protein target remain elusive. FBXO22 has recently been harnessed for TPD applications by degraders that covalently modify its cysteine residues. Here, we reveal that the aldehyde derivative of UNC10088 promotes cooperative binding of FBXO22 to NSD2, a histone methyltransferase and oncogenic protein, leading to a cryo-EM structure of the SKP1-CUL1-F-box (SCF)-FBXO22 complex with NSD2. This structure revealed a conformational change in the FBXO22 loop surrounding C326, further exposing the cysteine for covalent recruitment. Additional medicinal chemistry efforts led to the discovery of benzaldehyde-based non-prodrug degraders that similarly engage C326 of FBXO22 and potently degrade NSD2. Unlike many degraders, our molecules recruit NSD2 to a different surface of FBXO22 than the known FBXO22 substrate BACH1, allowing for concurrent complex formation and structural determination of SCF(FBXO22) bound to both the neosubstrate NSD2 and native substrate BACH1. Overall, we demonstrate the biochemical and structural basis for NSD2 degradation, revealing key principles for efficient and selective TPD by SCF(FBXO22). Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22.,Robertson KC, Amann SJ, Liu T, Funk AV, Wang X, Grishkovskaya I, Mehmood A, Tabor JR, Norris-Drouin JL, Arrowsmith CH, Collins JL, Miao Y, Emanuele MJ, Haselbach D, James LI, Brown NG Nat Commun. 2026 Apr 23. doi: 10.1038/s41467-026-72235-9. PMID:42026065[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
