9olb
Identification of ligands for E3 ligases using fragment-based methods
Structural highlights
FunctionTRAF4_HUMAN Adapter protein and signal transducer that links members of the tumor necrosis factor receptor (TNFR) family to different signaling pathways. Plays a role in the activation of NF-kappa-B and JNK, and in the regulation of cell survival and apoptosis. Regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. Required for normal skeleton development, and for normal development of the respiratory tract (By similarity). Required for activation of RPS6KB1 in response to TNF signaling. Modulates TRAF6 functions.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedHeterobifunctional molecules that induce targeted degradation have emerged as powerful tools in chemical biology, target validation, and drug discovery. Despite their promise, the field is constrained by the relative paucity of ligands available for E3 ligases. Expanding the ligand repertoire for E3 ligases and other components of ubiquitin-proteasome system could significantly broaden the scope of the targeted degradation field. In this study, we report the identification of ligands for non-essential E3 ligases that are preferentially expressed in cancer tissues relative to normal tissues. Using a protein-observed NMR-based fragment screen, an ideal technique for this purpose, we identified fragment ligands and characterized their binding modes by X-ray crystallography. These ligands represent promising starting points for further optimization toward the discovery of tumor-selective degraders that may enhance the therapeutic window targeting proteins for which inhibition or degradation is associated with systemic toxicity. Identification of ligands for E3 ligases with restricted expression using fragment-based methods.,Waterson AG, Lehmann BD, Lu Z, Sensintaffar JL, Olejniczak ET, Zhao B, Rietz T, Payne WG, Phan J, Fesik SW RSC Chem Biol. 2025 Oct 2. doi: 10.1039/d5cb00198f. PMID:41070186[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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