7V97

Arsenic-bound p53 DNA-binding domain mutant V272M

7V97 の概要

• エントリーDOI: 10.2210/pdb7v97/pdb
• 分子名称: Cellular tumor antigen p53, ARSENIC, ZINC ION, ... (4 entities in total)
• 機能のキーワード: keywords: dna-binding domain, complex, dna-bound, arsenic-bound, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 90711.91

構造登録者

Lu, M.,Xing, Y.F.,Wang, Z.Y.,Ni, Y.,Song, H.X. (登録日: 2021-08-24, 公開日: 2022-08-31, 最終更新日: 2023-11-29)

主引用文献

Song, H.,Wu, J.,Tang, Y.,Dai, Y.,Xiang, X.,Li, Y.,Wu, L.,Wu, J.,Liang, Y.,Xing, Y.,Yan, N.,Li, Y.,Wang, Z.,Xiao, S.,Li, J.,Zheng, D.,Chen, X.,Fang, H.,Ye, C.,Ma, Y.,Wu, Y.,Wu, W.,Li, J.,Zhang, S.,Lu, M.
Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties.
Sci Transl Med, 15:eabn9155-eabn9155, 2023

PubMed Abstract: Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

PubMed: 37018419
DOI: 10.1126/scitranslmed.abn9155

実験手法

X-RAY DIFFRACTION (2.02 Å)