9G5H

p53-Y220C Core Domain Covalently Bound to 2-chloro-5-cyanopyrazine Soaked at 5 mM

This is a non-PDB format compatible entry.

Summary for 9G5H

• Entry DOI: 10.2210/pdb9g5h/pdb
• Descriptor: Cellular tumor antigen p53, 5-chloranylpyrazine-2-carbonitrile, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (8 entities in total)
• Functional Keywords: covalent, snar, stabilization, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 51560.11

Authors

Stahlecker, J.,Klett, T.,Stehle, T.,Boeckler, F.M. (deposition date: 2024-07-17, release date: 2025-06-11, Last modification date: 2025-07-16)

Primary citation

Klett, T.,Stahlecker, J.,Schwer, M.,Jaag, S.J.,Masberg, B.,Knappe, C.,Lammerhofer, M.,Stehle, T.,Boeckler, F.M.
S N Ar Reactive Pyrazine Derivatives as p53-Y220C Cleft Binders with Diverse Binding Modes.
Drug Des Devel Ther, 19:4727-4753, 2025

PubMed Abstract: The tumor suppressor p53 is most commonly mutated in human cancer. The structural mutant in the β-sandwich of the protein, p53-Y220C, is the ninth most common p53 mutant. The p53-Y220C mutant has a solvent-accessible hydrophobic pocket, leading to thermal destabilization of the protein. Screening of our covalent fragment library (CovLib) revealed the highly reactive pyrazine derivatives SN006 and SN007, which arylate among other cysteines in p53, the mutation-generated Cys220. Herein, comprehensive structure-activity relationship (SAR) studies of these intrinsically reactive CovLib hits were performed, aiming to identify improved stabilizers for p53-Y220C, with a more balanced reactivity profile, diverse binding modes and a better potential for chemical optimization.

PubMed: 40599607
DOI: 10.2147/DDDT.S513792

Experimental method

X-RAY DIFFRACTION (1.65 Å)