8A92

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

Summary for 8A92

• Entry DOI: 10.2210/pdb8a92/pdb
• Descriptor: Cellular tumor antigen p53, 4-bromanyl-5-(trifluoromethyl)-1H-pyrazol-3-amine, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: halogen bond, small molecule, heflib, stabilizer, p53, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 50235.14

Authors

Stahlecker, J.,Braun, M.B.,Stehle, T.,Boeckler, F.M. (deposition date: 2022-06-27, release date: 2022-11-09, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.37 Å)