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| Main Authors: | , , |
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| Format: | Preprint |
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2026
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| Subjects: | |
| Online Access: | https://arxiv.org/abs/2601.11069 |
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| _version_ | 1866912827862679552 |
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| author | Zhou, Han Zhou, Tao Yan, Shiwei |
| author_facet | Zhou, Han Zhou, Tao Yan, Shiwei |
| contents | TP53 is the most frequently mutated tumor suppressor gene in human cancers, with mutations primarily in its DNA-binding domain (p53-DBD). Mutations in p53-DBD are categorized into hotspot mutations (resulting in complete loss-of-function) and non-hotspot mutations (inducing partial loss-of-function). However, the allosteric mechanisms underlying non-hotspot mutations remain elusive. Using p53 dimer as models, we constructed p53-WT, non-hotspot p53-E180R, and hotspot p53-R248W dimer-DNA complexes to compare the structural and functional impacts of these two mutation types. Our results reveal that both mutations weaken intramolecular interactions in p53-DBD and enhance structural flexibility. Specifically, E180R perturbs dimer interface interactions, impairing dimer stability and cooperative DNA binding; R248W disrupts interactions between the L3/L1 loops and DNA, leading to the loss of DNA-binding capacity. Steered molecular dynamics (SMD) simulations further confirm that both mutations accelerate p53 dimer dissociation, with E180R exerting the most prominent disruptive effect on the mechanical stability of the dimer interface. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2601_11069 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | Unraveling the Allosteric Mechanism and Mechanical Stability of Partial and Complete Loss-of-Function Mutations in p53 DNA-Binding Domain Zhou, Han Zhou, Tao Yan, Shiwei Biological Physics TP53 is the most frequently mutated tumor suppressor gene in human cancers, with mutations primarily in its DNA-binding domain (p53-DBD). Mutations in p53-DBD are categorized into hotspot mutations (resulting in complete loss-of-function) and non-hotspot mutations (inducing partial loss-of-function). However, the allosteric mechanisms underlying non-hotspot mutations remain elusive. Using p53 dimer as models, we constructed p53-WT, non-hotspot p53-E180R, and hotspot p53-R248W dimer-DNA complexes to compare the structural and functional impacts of these two mutation types. Our results reveal that both mutations weaken intramolecular interactions in p53-DBD and enhance structural flexibility. Specifically, E180R perturbs dimer interface interactions, impairing dimer stability and cooperative DNA binding; R248W disrupts interactions between the L3/L1 loops and DNA, leading to the loss of DNA-binding capacity. Steered molecular dynamics (SMD) simulations further confirm that both mutations accelerate p53 dimer dissociation, with E180R exerting the most prominent disruptive effect on the mechanical stability of the dimer interface. |
| title | Unraveling the Allosteric Mechanism and Mechanical Stability of Partial and Complete Loss-of-Function Mutations in p53 DNA-Binding Domain |
| topic | Biological Physics |
| url | https://arxiv.org/abs/2601.11069 |