Structural highlights
Function
FEM1B_HUMAN Component of an E3 ubiquitin-protein ligase complex, in which it may act as a substrate recognition subunit. Involved in apoptosis by acting as a death receptor-associated protein that mediates apoptosis. Also involved in glucose homeostasis in pancreatic islet. Functions as an adapter/mediator in replication stress-induced signaling that leads to the activation of CHEK1.[1] [2]
Publication Abstract from PubMed
Targeted protein degradation using PROTACs (PROteolysis TArgeting Chimeras) has emerged as a transformative therapeutic strategy, largely relying on a small number of E3 ubiquitin ligases such as CRBN and VHL. However, resistance, toxicity, and poor oral bioavailability limit the utility of PROTACs and highlight the need to expand the E3 ligase toolbox. Fem-1 homolog B (FEM1B) is a lesser-known E3 ligase that offers a promising alternative due to its broad expression and ability to recognize diverse degron motifs. Here, we describe the development of a stable construct of FEM1B, the results of a protein-observed NMR-based fragment screen using this construct, and the X-ray structures of some of the fragment hits when bound to the protein. From these results, new PROTACs utilizing FEM1B as the E3 ligase may be discovered, providing an alternative E3 ligase for targeted protein degradation.
Nuclear Magnetic Resonance-based fragment screen of the E3 ligase Fem-1 homolog B.,Katinas JM, Amporndanai K, Taylor AJ, Rose KL, Gareiss PC, Crespo RA, Phan J, Waterson AG, Fesik SW Protein Sci. 2025 Dec;34(12):e70365. doi: 10.1002/pro.70365. PMID:41229306[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chan SL, Tan KO, Zhang L, Yee KS, Ronca F, Chan MY, Yu VC. F1Aalpha, a death receptor-binding protein homologous to the Caenorhabditis elegans sex-determining protein, FEM-1, is a caspase substrate that mediates apoptosis. J Biol Chem. 1999 Nov 5;274(45):32461-8. PMID:10542291
- ↑ Sun TP, Shieh SY. Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress. Oncogene. 2009 May 7;28(18):1971-81. doi: 10.1038/onc.2009.58. Epub 2009 Mar 30. PMID:19330022 doi:http://dx.doi.org/10.1038/onc.2009.58
- ↑ Katinas JM, Amporndanai K, Taylor AJ, Rose KL, Gareiss PC, Crespo RA, Phan J, Waterson AG, Fesik SW. Nuclear Magnetic Resonance-based fragment screen of the E3 ligase Fem-1 homolog B. Protein Sci. 2025 Dec;34(12):e70365. PMID:41229306 doi:10.1002/pro.70365
