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NF-Kappa-B1 Bound with a Covalent Inhibitor
Structural highlights
FunctionNFKB1_HUMAN NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105.[1] Publication Abstract from PubMedCysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-kappaB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-kappaB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity. DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.,Takahashi M, Chong HB, Zhang S, Yang TY, Lazarov MJ, Harry S, Maynard M, Hilbert B, White RD, Murrey HE, Tsou CC, Vordermark K, Assaad J, Gohar M, Durr BR, Richter M, Patel H, Kryukov G, Brooijmans N, Alghali ASO, Rubio K, Villanueva A, Zhang J, Ge M, Makram F, Griesshaber H, Harrison D, Koglin AS, Ojeda S, Karakyriakou B, Healy A, Popoola G, Rachmin I, Khandelwal N, Neil JR, Tien PC, Chen N, Hosp T, van den Ouweland S, Hara T, Bussema L, Dong R, Shi L, Rasmussen MQ, Domingues AC, Lawless A, Fang J, Yoda S, Nguyen LP, Reeves SM, Wakefield FN, Acker A, Clark SE, Dubash T, Kastanos J, Oh E, Fisher DE, Maheswaran S, Haber DA, Boland GM, Sade-Feldman M, Jenkins RW, Hata AN, Bardeesy NM, Suva ML, Martin BR, Liau BB, Ott CJ, Rivera MN, Lawrence MS, Bar-Peled L Cell. 2024 Apr 17:S0092-8674(24)00318-0. doi: 10.1016/j.cell.2024.03.027. PMID:38653237[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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