3TC5

Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives

3TC5 の概要

• エントリーDOI: 10.2210/pdb3tc5/pdb
• 関連するPDBエントリー: 1PIN 2ITK 2Q5A 2ZR6
• 分子名称: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, (11alpha,16alpha)-9-fluoro-11,17-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-yl dihydrogen phosphate, HEXAETHYLENE GLYCOL, ... (4 entities in total)
• 機能のキーワード: pin1 mutant (r14a), oncogenic transformation, small molecule, cell cycle, rotamase, phosphoprotein, nucleus, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q13526
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19222.24

構造登録者

Graeber, M.,Janczyk, W.,Sperl, B.,Elumalai, N.,Kozany, C.,Hausch, F.,Holak, T.A.,Berg, T. (登録日: 2011-08-08, 公開日: 2011-08-31, 最終更新日: 2023-09-13)

主引用文献

Graber, M.,Janczyk, W.,Sperl, B.,Elumalai, N.,Kozany, C.,Hausch, F.,Holak, T.A.,Berg, T.
Selective targeting of disease-relevant protein binding domains by o-phosphorylated natural product derivatives.
Acs Chem.Biol., 6:1008-1014, 2011

PubMed Abstract: Phosphorylation-dependent protein binding domains are crucially important for intracellular signaling pathways and thus highly relevant targets in chemical biology. By screening of chemical libraries against 12 structurally diverse phosphorylation-dependent protein binding domains, we have identified fosfosal and dexamethasone-21-phosphate as selective inhibitors of two antitumor targets: the SH2 domain of the transcription factor STAT5b and the substrate-binding domain of the peptidyl-prolyl isomerase Pin1, respectively. Both compounds are phosphate prodrugs with documented clinical use as anti-inflammatory agents in humans and were discovered with a high hit rate from a small subgroup within the screening library. Our study indicates O-phosphorylation of appropriately preselected natural products or natural product derivatives as a generally applicable strategy for the identification of non-reactive and non-peptidic ligands of phosphorylation-dependent protein binding domains. Moreover, our data indicate that it would be advisable to monitor the bioactivities of clinically used prodrugs in their uncleaved state against phosphorylation-dependent protein binding domains.

PubMed: 21797253
DOI: 10.1021/cb2001796

実験手法

X-RAY DIFFRACTION (1.4 Å)