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7DHZ

Arsenic-bound p53 DNA-binding domain mutant R249S

Summary for 7DHZ
Entry DOI10.2210/pdb7dhz/pdb
DescriptorCellular tumor antigen p53, GLYCEROL, ARSENIC, ... (5 entities in total)
Functional Keywordstumour suppressor, transcription factor, transcription
Biological sourceHomo sapiens (Human)
Total number of polymer chains2
Total formula weight45427.88
Authors
Chen, S.,Lu, M. (deposition date: 2020-11-18, release date: 2021-03-03, Last modification date: 2023-11-29)
Primary citationChen, S.,Wu, J.L.,Liang, Y.,Tang, Y.G.,Song, H.X.,Wu, L.L.,Xing, Y.F.,Yan, N.,Li, Y.T.,Wang, Z.Y.,Xiao, S.J.,Lu, X.,Chen, S.J.,Lu, M.
Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site.
Cancer Cell, 39:225-239.e8, 2021
Cited by
PubMed Abstract: 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 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.
PubMed: 33357454
DOI: 10.1016/j.ccell.2020.11.013
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.74 Å)
Structure validation

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