7B4E

Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human p53DBD-R282W mutant bound to DNA and MQ: R282W-DNA-MQ

Summary for 7B4E

• Entry DOI: 10.2210/pdb7b4e/pdb
• Related: 6ZNC 7B46 7B47 7B48 7B49 7B4A 7B4B 7B4C 7B4D 7B4F 7B4G 7B4H 7B4N
• Descriptor: Cellular tumor antigen p53, DNA target, ZINC ION, ... (8 entities in total)
• Functional Keywords: p53, tumor suppressor, dna binding protein, protein dna complex, michael acceptor, michael reaction, protein-drug complex, protein-dna-drug complex, loop-sheet-helix motif, dna target, activator, transcription, hoogsteen base-pairing
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 26810.32

Authors

Degtjarik, O.,Rozenberg, H.,Shakked, Z. (deposition date: 2020-12-02, release date: 2021-12-08, Last modification date: 2024-01-31)

Primary citation

Degtjarik, O.,Golovenko, D.,Diskin-Posner, Y.,Abrahmsen, L.,Rozenberg, H.,Shakked, Z.
Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).
Nat Commun, 12:7057-7057, 2021

PubMed Abstract: In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.

PubMed: 34862374
DOI: 10.1038/s41467-021-27142-6

Experimental method

X-RAY DIFFRACTION (1.58 Å)