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Hot-spot mutants of p53 core domain evince characteristic local structural changes
Open accessAbstract
Most of the oncogenic mutations in the tumor suppressor p53 map to its DNA-binding (core) domain. It is thus a potential target in cancer therapy for rescue by drugs. To begin to understand how mutation inactivates p53 and hence to provide a structural basis for drug design, we have compared structures of wild-type and mutant p53 core domains in solution by NMR spectroscopy. Structural changes introduced by five hot-spot mutations (V143A, G245S, R248Q, R249S, and R273H) were monitored by chemical-shift changes. Only localized changes are observed for G245S, R248Q, R249S, and R273H, suggesting that the overall tertiary folds of these mutant proteins are similar to that of wild type. Structural changes in R273H are found mainly in the loop–sheet–helix motif and the loop L3 of the core domain. Mutations in L3 (G245S, R248Q, and R249S) introduce structural changes in the loop L2 and L3 as well as terminal residues of strands 4, 9, and 10. It is noteworthy that R248Q, which is often regarded as a contact mutant that affects only interactions with DNA, introduces structural changes as extensive as the other loop L3 mutations (G245S and R249S). These changes suggest that R248Q is also a structural mutant that perturbs the structure of loop L2–L3 regions of the p53 core domain. In contrast to other mutants, replacement of the core residue valine 143 to alanine causes chemical-shift changes in almost all residues in the β-sandwich and the DNA-binding surface. Long-range effects of V143A mutation may affect the specificity of DNA binding.
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TL;DR
NMR spectroscopy of the p53 core domain shows that five common hot-spot mutants cause characteristic local structural changes rather than global unfolding. R248Q, often considered only a DNA-contact mutant, also perturbs the L2–L3 region, while V143A produces long-range changes in the β-sandwich and DNA-binding surface.
Key findings
- Of 200 backbone amide signals, 176 were assigned; solution secondary structure matched the crystal structure, and residues 294–312 had random-coil shifts, indicating an unstructured C-terminal tail.
- G245S, R248Q, R249S, and R273H showed only localized chemical-shift changes, suggesting overall folds similar to wild type. R273H changes mapped mainly to the loop–sheet–helix motif and L3, including residues 281, 282, 285, and 286 after loss of the Arg-273–Asp-281 salt bridge.
- L3 mutations G245S, R248Q, and R249S introduced changes in L2 and L3 and terminal residues of strands 4, 9, and 10. R248Q produced changes as extensive as R249S; both are ≈2 kcal/mol less stable than wild type.
- V143A caused chemical-shift changes in almost all residues of the β-sandwich and the DNA-binding surface, which the authors suggest may affect DNA-binding specificity.
Methods
- Solution NMR compared wild-type and five mutant human p53 core domains (residues 94–312): V143A, G245S, R248Q, R249S, and R273H.
- Samples included 15N-labeled proteins and an 80% 2H, uniformly 13C,15N-labeled sample; 1H–15N HSQC spectra were acquired at 293 K, and triple-resonance experiments at 298 K on Bruker 600- and 800-MHz spectrometers.
- Backbone assignments used triple-resonance experiments and NOEs; structural changes were monitored by chemical-shift changes, with secondary structure assessed from ΔCα − ΔCβ deviations from random-coil values.
Limitations
- Stated in the paper: whether PAb240 can bind a partly unfolded form is still under active debate, and the authors note that comparing backbone dynamics of wild type and hot-spot mutants “may prove informative.”
- Evident from the text: conclusions rest on chemical-shift changes rather than full high-resolution structures of the mutants.
- Evident from the text: only five hot-spot mutants were studied, and the NMR measurements were performed at 20°C/293 K without direct DNA-binding or functional assays in this paper.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Structural changes in R273H are found mainly in the loop–sheet–helix motif and the loop L3 of the core domain.”
- Also stated in: § RESULTS · plain
“Chemical-shift changes are mainly found in the loop–sheet–helix motif and the L3 loop of core domain (Fig. 3B).”
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In the paper
“Our NMR data suggest that, at 20°C, R249S and G245S (both PAb240+) fold into structures in a manner similar to the wild type.”
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In the paper
“suggesting the structure of p53 core domain in solution is similar to that in crystal structure (1).”
What the sources say
- Not checked yetcites [1] Cho Y, Gorina S, Jeffrey P D, Pavletich N P. Science. 1994;265:346–355. doi: 10.1126/science.8023157. [DOI] [PubMed] [Google Scholar] source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“It is noteworthy that R248Q, which is often regarded as a contact mutant that affects only interactions with DNA, introduces structural changes as extensive as the other loop L3 mutations (G245S and R249S).”
- Also stated in: § RESULTS · plain
“It is intriguing to find that pattern of chemical-shift changes for R248Q are as extensive as those for R249S.”
plainstates an association- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption not shown here.
- Also stated in: § RESULTS · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast to other mutants, replacement of the core residue valine 143 to alanine causes chemical-shift changes in almost all residues in the β-sandwich and the DNA-binding surface.”
- Also stated in: § RESULTS · plain
“In contrast to other mutants studied, extensive chemical changes are found for almost all residues in the β-sandwich (Fig. 3B).”
plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the citing paper
“Recent NMR and MD simulation studies have also revealed two key effects: disruption of DNA contact and structural destabilization 25-28.”
From Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer (2026) · cites this paper as [27]
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Brown, K., Jenkins, L. M. M., Crooks, D. R., Surman, D. R., Mazur, S. J., Xu, Y., Arimilli, B. S., Yang, Y., Lane, A. N., Fan, T. W. ‐., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1094210 · Cited by 5
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Metadata
- Authors
- Wong, K.-B., DeDecker, B. S., Freund, S. M. V., Proctor, M. R., Bycroft, M., & Fersht, A. R.
- Affiliations
- University of Cambridge (GB)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-07-20
- Volume
- 96
- Issue
- 15
- Pages
- 8438-8442
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC17534
- OpenAlex
- W2093865758
- Cited by
- 221
- References
- 24
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 3 · 2023: 10 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 6 · 2017: 9 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 8 · 2012: 7
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- p53, p53 core domain, hot spot mutations, oncogenic mutations, tumor suppressor, protein structure, solution structure, chemical shift changes, DNA binding specificity, drug design
- MeSH terms
- Binding Sites, DNA-Binding Proteins, Humans, Models, Molecular, Mutation, Neoplasms, Magnetic Resonance Spectroscopy, Tumor Suppressor Protein p53, Protein Structure, Secondary
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-13, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-13 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
