8TQD

NF-Kappa-B1 Bound with a Covalent Inhibitor

Summary for 8TQD

• Entry DOI: 10.2210/pdb8tqd/pdb
• Descriptor: Nuclear factor NF-kappa-B p105 subunit, 1-(2-bromo-4-chlorophenyl)-N-{(3S)-1-[(E)-iminomethyl]pyrrolidin-3-yl}methanesulfonamide (3 entities in total)
• Functional Keywords: transcription factor, dna binding protein, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 23118.84

Authors

Hilbert, B.J. (deposition date: 2023-08-07, release date: 2024-04-24, Last modification date: 2024-11-06)

Primary citation

Takahashi, M.,Chong, H.B.,Zhang, S.,Yang, T.Y.,Lazarov, M.J.,Harry, S.,Maynard, M.,Hilbert, B.,White, R.D.,Murrey, H.E.,Tsou, C.C.,Vordermark, K.,Assaad, J.,Gohar, M.,Durr, B.R.,Richter, M.,Patel, H.,Kryukov, G.,Brooijmans, N.,Alghali, A.S.O.,Rubio, K.,Villanueva, A.,Zhang, J.,Ge, M.,Makram, F.,Griesshaber, H.,Harrison, D.,Koglin, A.S.,Ojeda, S.,Karakyriakou, B.,Healy, A.,Popoola, G.,Rachmin, I.,Khandelwal, N.,Neil, J.R.,Tien, P.C.,Chen, N.,Hosp, T.,van den Ouweland, S.,Hara, T.,Bussema, L.,Dong, R.,Shi, L.,Rasmussen, M.Q.,Domingues, A.C.,Lawless, A.,Fang, J.,Yoda, S.,Nguyen, L.P.,Reeves, S.M.,Wakefield, F.N.,Acker, A.,Clark, S.E.,Dubash, T.,Kastanos, J.,Oh, E.,Fisher, D.E.,Maheswaran, S.,Haber, D.A.,Boland, G.M.,Sade-Feldman, M.,Jenkins, R.W.,Hata, A.N.,Bardeesy, N.M.,Suva, M.L.,Martin, B.R.,Liau, B.B.,Ott, C.J.,Rivera, M.N.,Lawrence, M.S.,Bar-Peled, L.
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
Cell, 187:2536-, 2024

PubMed Abstract: Cysteine-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-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 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.

PubMed: 38653237
DOI: 10.1016/j.cell.2024.03.027

Experimental method

X-RAY DIFFRACTION (2.02 Å)