Mechanistic Insights into the Allosteric Regulation of P53 Y220C by Small-Molecule Stabilizers

作者：Yiming Wen, Buying Niu, Jingyi Meng, D. Chen, Xutong Li, Sulin Zhang, Hans Ågren, Mingyue Zheng, Dan Teng · 发表于：Journal of Chemical Information and Modeling · 年份：2025 · DOI：10.1021/acs.jcim.5c02062 · 被引用次数：3 · 研究领域：Cancer-related Molecular Pathways、Microtubule and mitosis dynamics、Hippo pathway signaling and YAP/TAZ

The p53 Y220C mutation is a recurrent hotspot alteration that induces local unfolding and long-range functional disruption, compromising its tumor suppressor activity. While small-molecule stabilizers targeting this mutation have shown therapeutic promise, their underlying allosteric regulatory mechanisms remain poorly defined. Here, we investigate two p53 Y220C stabilizers with near-identical scaffolds but over 60-fold difference in activity, serving as a model to dissect the structural basis of differential efficacy. Through microsecond-scale molecular dynamics simulations and residue interaction network analysis, we reveal that the more active compound not only engages the mutation-induced cavity but also restores long-range cooperative networks and DNA-binding interfaces by rewiring key allosteric communication pathways disrupted by the mutation. Our results uncover a multilayered allosteric rescue mechanism involving dynamic pocket engagement, hydrophobic core reconstruction, and intramolecular signal reactivation. These findings move beyond conventional binding-affinity explanations and highlight the importance of network-level conformational regulation in mutant p53 rescue. This work establishes a mechanistic foundation for rational stabilizer design, proposing a new strategy centered on allosteric network restoration and mutation-adaptable anchoring. It offers broader implications for targeting conformationally unstable transcription factors previously considered "und...