7EAX

Crystal complex of p53-V272M and antimony ion

7EAX の概要

• エントリーDOI: 10.2210/pdb7eax/pdb
• 分子名称: Cellular tumor antigen p53, ZINC ION, ANTIMONY (III) ION, ... (4 entities in total)
• 機能のキーワード: tumor suppressor p53, structural stabilization, antitumor protein
• 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: 88312.22

構造登録者

Lu, M.,Tang, Y. (登録日: 2021-03-08, 公開日: 2022-02-16, 最終更新日: 2023-11-29)

主引用文献

Tang, Y.,Song, H.,Wang, Z.,Xiao, S.,Xiang, X.,Zhan, H.,Wu, L.,Wu, J.,Xing, Y.,Tan, Y.,Liang, Y.,Yan, N.,Li, Y.,Li, J.,Wu, J.,Zheng, D.,Jia, Y.,Chen, Z.,Li, Y.,Zhang, Q.,Zhang, J.,Zeng, H.,Tao, W.,Liu, F.,Wu, Y.,Lu, M.
Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations.
Cell Rep, 39:110622-110622, 2022

PubMed Abstract: The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.

PubMed: 35417717
DOI: 10.1016/j.celrep.2022.110622

実験手法

X-RAY DIFFRACTION (2.55 Å)