ArticleScientific reports2019
Rational design using sequence information only produces a peptide that binds to the intrinsically disordered region of p53.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 22 citations in OpenAlex.
- The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.Nature communications · 2025Article
- Insight into Protein Engineering: FromCurrent pharmaceutical design · 2025Review
- Intrinsic Disorder and Other Malleable Arsenals of Evolved Protein Multifunctionality.Journal of molecular evolution · 2024Review
- Rational design of phase separating peptides based on phase separating protein sequence of p53.Scientific reports · 2023Article
- Rational peptide design for regulating liquid-liquid phase separation on the basis of residue-residue contact energy.Scientific reports · 2022Article
- Characterization of design grammar of peptides for regulating liquid droplets and aggregates of FUS.Scientific reports · 2021Article
- Recent Progress Using De Novo Design to Study Protein Structure, Design and Binding Interactions.Life (Basel, Switzerland) · 2021Review
- Single-Molecule Microscopy Meets Molecular Dynamics Simulations for Characterizing the Molecular Action of Proteins on DNA and in Liquid Condensates.Frontiers in molecular biosciences · 2021Review
- Transient binding and jumping dynamics of p53 along DNA revealed by sub-millisecond resolved single-molecule fluorescence tracking.Scientific reports · 2020Article
- How p53 Molecules Solve the Target DNA Search Problem: A Review.International journal of molecular sciences · 2020Review
- A novel mode of interaction between intrinsically disordered proteins.Biophysics and physicobiology · 2020Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intrinsically disordered regions (IDRs) of proteins are involved in many diseases. The rational drug design against disease-mediating proteins is often based on the 3D structure; however, the flexible structure of IDRs hinders the use of such structure-based design methods. Here, we developed a rational design method to obtain a peptide that can bind an IDR using only sequence information based on the statistical contact energy of amino acid pairs. We applied the method to the disordered C-terminal domain of the tumor suppressor p53. Titration experiments revealed that one of the designed peptides, DP6, has a druggable affinity of ~1 μM to the p53 C-terminal domain. NMR spectroscopy and molecular dynamics simulation revealed that DP6 selectively binds to the vicinity of the target sequence in the C-terminal domain of p53. DP6 inhibits the nonspecific DNA binding of a tetrameric form of the p53 C-terminal domain, but does not significantly affect the specific DNA binding of a tetrameric form of the p53 core domain. Single-molecule measurements revealed that DP6 retards the 1D sliding of p53 along DNA, implying modulation of the target searching of p53. Statistical potential-based design may be useful in designing peptides that target IDRs for therapeutic purposes.
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