2026-10-16T08:43:06Z https://data.mendeley.com/oai

oai:data.mendeley.com/yy7hxp5td4.1 2020-11-20T13:56:40Z

Liang, Ying Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site Mendeley Data TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly-applicable allosteric sites. Here we report the identification of small molecules including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall β-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the most frequent twenty-five p53 mutations informs patient stratification for clinical exploration. Our results provide mechanistic basis for repurposing ATO to target p53 mutations for widely-applicable yet personalized cancer therapies. Drug Discovery Crystallography Structural Biology Tumor Suppressor Protein Transcription Factor Targeted Therapy Arsenic P53 Chen, Shuo Wu, Jia-Le Tang, Yi-Gang Song, Hua-Xin Wu, Li-Li Xing, Yang-Fei Yan, Ni Li, Yun-Tong Wang, Zheng-Yuan Xiao, Shu-Jun Lu, Xin Chen, Sai-Juan Lu, Min Dataset doi:10.17632/yy7hxp5td4.1 oai:data.mendeley.com/yy7hxp5td4.1 Attribution-NonCommercial 3.0 Unported https://creativecommons.org/licenses/by-nc/3.0 https://data.mendeley.com/datasets/yy7hxp5td4 2020-11-20T13:56:40Z