6E22

Displacement of WDR5 from chromatin by a pharmacological WIN site inhibitor with picomolar affinity

6E22 の概要

• エントリーDOI: 10.2210/pdb6e22/pdb
• 関連するPDBエントリー: 6D9X
• 分子名称: WD repeat-containing protein 5, 3-{[(4,5-dihydro-1H-imidazol-2-yl)amino]methyl}-N-[(3,5-dimethoxyphenyl)methyl]-4-fluorobenzamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: wdr5, win-site, fragment screening, structure-based design, mixed-lineage leukemia, dna binding protein, dna binding protein-inhibitor complex, gene regulation, gene regulation-inhibitor complex, gene regulation/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69746.95

構造登録者

Phan, J.,Fesik, S.W. (登録日: 2018-07-10, 公開日: 2019-03-13, 最終更新日: 2023-10-11)

主引用文献

Aho, E.R.,Wang, J.,Gogliotti, R.D.,Howard, G.C.,Phan, J.,Acharya, P.,Macdonald, J.D.,Cheng, K.,Lorey, S.L.,Lu, B.,Wenzel, S.,Foshage, A.M.,Alvarado, J.,Wang, F.,Shaw, J.G.,Zhao, B.,Weissmiller, A.M.,Thomas, L.R.,Vakoc, C.R.,Hall, M.D.,Hiebert, S.W.,Liu, Q.,Stauffer, S.R.,Fesik, S.W.,Tansey, W.P.
Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity.
Cell Rep, 26:2916-2928.e13, 2019

PubMed Abstract: The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.

PubMed: 30865883
DOI: 10.1016/j.celrep.2019.02.047

実験手法

X-RAY DIFFRACTION (1.6 Å)