7B49

Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human p53DBD-R273H mutant bound to DNA and MQ: R273H-DNA-MQ

7B49 の概要

• エントリーDOI: 10.2210/pdb7b49/pdb
• 関連するPDBエントリー: 6ZNC 7B46 7B47 7B48 7B4A 7B4B 7B4C 7B4D 7B4E 7B4F 7B4G 7B4H 7B4N
• 分子名称: Cellular tumor antigen p53, DNA target, ZINC ION, ... (9 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 53572.76

構造登録者

Rozenberg, H.,Degtjarik, O.,Shakked, Z. (登録日: 2020-12-02, 公開日: 2021-12-08, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.42 Å)