8TQD

NF-Kappa-B1 Bound with a Covalent Inhibitor

8TQD の概要

• エントリーDOI: 10.2210/pdb8tqd/pdb
• 分子名称: 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)
• 機能のキーワード: transcription factor, dna binding protein, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23118.84

構造登録者

Hilbert, B.J. (登録日: 2023-08-07, 公開日: 2024-04-24, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.02 Å)