8RBA

p53-Y220C Core Domain Covalently Bound to 2,5,6-trifluoropyridine-3-carbonitrile Soaked at 5 mM

8RBA の概要

• エントリーDOI: 10.2210/pdb8rba/pdb
• 関連するPDBエントリー: 8RBB 8RBC
• 分子名称: Cellular tumor antigen p53, 2,5-bis(fluoranyl)pyridine-3-carbonitrile, DI(HYDROXYETHYL)ETHER, ... (8 entities in total)
• 機能のキーワード: covalent, snar, stabilization, 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: 51448.93

構造登録者

Stahlecker, J.,Klett, T.,Stehle, T.,Boeckler, F.M. (登録日: 2023-12-04, 公開日: 2024-11-27, 最終更新日: 2025-01-01)

主引用文献

Klett, T.,Stahlecker, J.,Jaag, S.,Masberg, B.,Knappe, C.,Lammerhofer, M.,Coles, M.,Stehle, T.,Boeckler, F.M.
Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.
Acs Pharmacol Transl Sci, 7:3984-3999, 2024

PubMed Abstract: The tumor suppressor p53 is frequently mutated in human cancers. The Y220C mutant is the ninth most common p53 cancer mutant and is classified as a structural mutant, as it leads to strong thermal destabilization and degradation by creating a solvent-accessible hydrophobic cleft. To identify small molecules that thermally stabilize p53, we employed DSF to screen SAr-type electrophiles from our covalent fragment library (CovLib) for binding to different structural (Y220C, R282W) and DNA contact (R273H) mutants of p53. The reactive fragments SN001, SN006, and SN007 were detected to specifically stabilize Y220C, indicating the arylation of Cys220 in the mutational cleft, as confirmed by X-ray crystallography. The fragments occupy the central cavity and mimic the ring system of the WT tyrosine lost by the mutation. Surpassing previously reported noncovalent ligands, SN001 stabilized T-p53C-Y220C concentration-dependently up to 4.45 °C and, due to its small size, represents a promising starting point for optimization.

PubMed: 39698266
DOI: 10.1021/acsptsci.4c00414

実験手法

X-RAY DIFFRACTION (1.57 Å)