Mechanistic Insights into the Allosteric Regulation of P53 Y220C by Small-Molecule Stabilizers
文献类型：期刊论文
| 作者 | Wen, Yiming2,3,4; Niu, Buying4,5; Meng, Jingyi1; Chen, Danye7; Li, Xutong4,5; Zhang, Suilin4,5; Agren, Hans6; Zheng, Mingyue4,5; Teng, Dan5 |
| 刊名 | JOURNAL OF CHEMICAL INFORMATION AND MODELING
 |
| 出版日期 | 2025-12-08 |
| 卷号 | 65期号:23页码:12945-12958 |
| ISSN号 | 1549-9596 |
| DOI | 10.1021/acs.jcim.5c02062 |
| 英文摘要 | 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 "undruggable". |
| WOS关键词 | CANCER ; PROTEIN ; PATHWAY ; PARAMETERS |
| 资助项目 | National Key Research and Development Program of China[2022YFC3400504] ; National Key Research and Development Program of China[2023YFC2305904] ; National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; National Natural Science Foundation of China[82404513] ; National Natural Science Foundation of China[82204278] ; Postdoctoral Fellowship Program of CPSF[GZC20232846] ; China Postdoctoral Science Foundation[2024M763419] ; SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program[E2G805H] ; Shanghai Municipal Science and Technology Major Project ; National Academic Infrastructure for Supercomputing in Sweden (NAISS)[NAISS 2024/5-552] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:001621919400001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322019]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Zheng, Mingyue; Teng, Dan |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 2.Lingang Lab, Shanghai 200031, Peoples R China 3.Shanghai Tech Univ, Sch Phys Sci & Technol, Shanghai 200031, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Uppsala Univ, Dept Phys & Astron, Div X Ray Photon Sci, S-75120 Uppsala, Sweden 7.Univ Cambridge, Dept Pharmacol, Cambridge CB2 1QR, England |
| 推荐引用方式 GB/T 7714 | Wen, Yiming,Niu, Buying,Meng, Jingyi,et al. Mechanistic Insights into the Allosteric Regulation of P53 Y220C by Small-Molecule Stabilizers[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2025,65(23):12945-12958. |
| APA | Wen, Yiming.,Niu, Buying.,Meng, Jingyi.,Chen, Danye.,Li, Xutong.,...&Teng, Dan.(2025).Mechanistic Insights into the Allosteric Regulation of P53 Y220C by Small-Molecule Stabilizers.JOURNAL OF CHEMICAL INFORMATION AND MODELING,65(23),12945-12958. |
| MLA | Wen, Yiming,et al."Mechanistic Insights into the Allosteric Regulation of P53 Y220C by Small-Molecule Stabilizers".JOURNAL OF CHEMICAL INFORMATION AND MODELING 65.23(2025):12945-12958. |
入库方式： OAI收割
来源：上海药物研究所
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