8CG7
Structure of p53 cancer mutant Y220C with arylation at Cys182 and Cys277
This is a non-PDB format compatible entry.
Summary for 8CG7
| Entry DOI | 10.2210/pdb8cg7/pdb |
| Descriptor | Cellular tumor antigen p53, ZINC ION, 5-iodanyl-2-methylsulfonyl-pyrimidine, ... (5 entities in total) |
| Functional Keywords | p53 cancer mutation, protein stability, covalent modification, cys-arylation, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 50390.81 |
| Authors | Balourdas, D.I.,Pichon, M.M.,Baud, M.G.J.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2023-02-03, release date: 2023-12-13, Last modification date: 2024-11-13) |
| Primary citation | Pichon, M.M.,Drelinkiewicz, D.,Lozano, D.,Moraru, R.,Hayward, L.J.,Jones, M.,McCoy, M.A.,Allstrum-Graves, S.,Balourdas, D.I.,Joerger, A.C.,Whitby, R.J.,Goldup, S.M.,Wells, N.,Langley, G.J.,Herniman, J.M.,Baud, M.G.J. Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation. Bioconjug.Chem., 34:1679-1687, 2023 Cited by PubMed Abstract: Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine -arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable -heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SAr reactivity , covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically -arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery. PubMed: 37657082DOI: 10.1021/acs.bioconjchem.3c00322 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.53 Å) |
Structure validation
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