8A92

p53-Y220C Core Domain in Complex with a Bromo-trifluoro-pyrazole-amine

8A92 の概要

• エントリーDOI: 10.2210/pdb8a92/pdb
• 分子名称: Cellular tumor antigen p53, 4-bromanyl-5-(trifluoromethyl)-1H-pyrazol-3-amine, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (6 entities in total)
• 機能のキーワード: halogen bond, small molecule, heflib, stabilizer, p53, cell cycle
• 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: 50235.14

構造登録者

Stahlecker, J.,Braun, M.B.,Stehle, T.,Boeckler, F.M. (登録日: 2022-06-27, 公開日: 2022-11-09, 最終更新日: 2024-01-31)

主引用文献

Stahlecker, J.,Klett, T.,Schwer, M.,Jaag, S.,Dammann, M.,Ernst, L.N.,Braun, M.B.,Zimmermann, M.O.,Kramer, M.,Lammerhofer, M.,Stehle, T.,Coles, M.,Boeckler, F.M.
Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C.
Rsc Med Chem, 13:1575-1586, 2022

PubMed Abstract: The cellular tumor antigen p53 is a key component in cell cycle control. The mutation Y220C heavily destabilizes the protein thermally but yields a druggable crevice. We have screened the diversity-optimized halogen-enriched fragment library against T-p53C-Y220C with STD-NMR and DSF to identify hits, which we validated by H,N-HSQC NMR. We could identify four hits binding in the Y220C cleft, one hit binding covalently and four hits binding to an uncharacterized binding site. Compound 1151 could be crystallized showing a flip of C220 and thus opening subsite 3. Additionally, 4482 was identified to alkylate cysteines. Data shows that the diversity-optimized HEFLib leads to multiple diverse hits. The identified scaffolds can be used to further optimize interactions with T-p53C-Y220C and increase thermal stability.

PubMed: 36561072
DOI: 10.1039/d2md00246a

実験手法

X-RAY DIFFRACTION (1.37 Å)