Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation
IntroductionIn the era of targeted therapies, molecules for the reactivation of the oncosuppressor p53 in human cancer have not yet reached FDA or EMA approval. Recently, the interaction region of the MDM2/MDM4 heterodimer, the most efficient inhibitor of p53 levels and function, has been successful...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Chemical Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchbi.2025.1576640/full |
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| author | Marika Attili Marika Attili Sonia Valentini Sonia Valentini Maria Pesavento Maria Pesavento Marco Ballarotto Viviana Scognamiglio Alfredo Pontecorvi Antonio Macchiarulo Fulvio Saccoccia Fabiola Moretti |
| author_facet | Marika Attili Marika Attili Sonia Valentini Sonia Valentini Maria Pesavento Maria Pesavento Marco Ballarotto Viviana Scognamiglio Alfredo Pontecorvi Antonio Macchiarulo Fulvio Saccoccia Fabiola Moretti |
| author_sort | Marika Attili |
| collection | DOAJ |
| description | IntroductionIn the era of targeted therapies, molecules for the reactivation of the oncosuppressor p53 in human cancer have not yet reached FDA or EMA approval. Recently, the interaction region of the MDM2/MDM4 heterodimer, the most efficient inhibitor of p53 levels and function, has been successfully targeted. Disruption of the heterodimer activated p53 oncosuppressive function in vitro and in vivo. Despite these encouraging results, further studies on the MDM2/MDM4 interaction region have yet to progress.MethodsHere, we undertook a detailed bioinformatic and biochemical analysis of this region. Using molecular dynamics simulation followed by umbrella sampling.Results and discussionWe characterized a short peptide and modified derivatives with increased binding affinity and pharmacodynamics features compared to previous molecules. Our results uncover the intrinsic plasticity of the MDM2 RING domain through different binding clefts and provide evidence of its ability to host different peptides by key residues. This data may guide the development of next-generation therapeutic inhibitors. |
| format | Article |
| id | doaj-art-8fba43358eec4084b53e1bc73eb42cfb |
| institution | DOAJ |
| issn | 2813-530X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemical Biology |
| spelling | doaj-art-8fba43358eec4084b53e1bc73eb42cfb2025-08-20T03:09:39ZengFrontiers Media S.A.Frontiers in Chemical Biology2813-530X2025-05-01410.3389/fchbi.2025.15766401576640Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivationMarika Attili0Marika Attili1Sonia Valentini2Sonia Valentini3Maria Pesavento4Maria Pesavento5Marco Ballarotto6Viviana Scognamiglio7Alfredo Pontecorvi8Antonio Macchiarulo9Fulvio Saccoccia10Fabiola Moretti11Institute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Monterotondo, Rome, ItalyPh.D. Course in Sciences of Nutrition, Metabolism, Aging and Gender-related Pathologies, Catholic University Sacro Cuore, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Monterotondo, Rome, ItalyPh.D. Course in Sciences of Nutrition, Metabolism, Aging and Gender-related Pathologies, Catholic University Sacro Cuore, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Monterotondo, Rome, ItalyPh.D. Course in Sciences of Nutrition, Metabolism, Aging and Gender-related Pathologies, Catholic University Sacro Cuore, Rome, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Perugia, ItalyInstitute of Crystallography, National Research Council of Italy (CNR), Rome, ItalyDepartment of Medicine and Translational Surgery, Catholic University of Roma, Rome, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Perugia, ItalyInstitute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Monterotondo, Rome, ItalyInstitute of Biochemistry and Cell Biology, National Research Council of Italy (CNR), Monterotondo, Rome, ItalyIntroductionIn the era of targeted therapies, molecules for the reactivation of the oncosuppressor p53 in human cancer have not yet reached FDA or EMA approval. Recently, the interaction region of the MDM2/MDM4 heterodimer, the most efficient inhibitor of p53 levels and function, has been successfully targeted. Disruption of the heterodimer activated p53 oncosuppressive function in vitro and in vivo. Despite these encouraging results, further studies on the MDM2/MDM4 interaction region have yet to progress.MethodsHere, we undertook a detailed bioinformatic and biochemical analysis of this region. Using molecular dynamics simulation followed by umbrella sampling.Results and discussionWe characterized a short peptide and modified derivatives with increased binding affinity and pharmacodynamics features compared to previous molecules. Our results uncover the intrinsic plasticity of the MDM2 RING domain through different binding clefts and provide evidence of its ability to host different peptides by key residues. This data may guide the development of next-generation therapeutic inhibitors.https://www.frontiersin.org/articles/10.3389/fchbi.2025.1576640/fulltarget p53peptideMDM2MDM4 (MDMX)umbrella sampling |
| spellingShingle | Marika Attili Marika Attili Sonia Valentini Sonia Valentini Maria Pesavento Maria Pesavento Marco Ballarotto Viviana Scognamiglio Alfredo Pontecorvi Antonio Macchiarulo Fulvio Saccoccia Fabiola Moretti Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation Frontiers in Chemical Biology target p53 peptide MDM2 MDM4 (MDMX) umbrella sampling |
| title | Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation |
| title_full | Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation |
| title_fullStr | Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation |
| title_full_unstemmed | Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation |
| title_short | Exploring the heterodimer MDM2/MDM4 interaction region uncovers high-affinity peptides for therapeutic p53-reactivation |
| title_sort | exploring the heterodimer mdm2 mdm4 interaction region uncovers high affinity peptides for therapeutic p53 reactivation |
| topic | target p53 peptide MDM2 MDM4 (MDMX) umbrella sampling |
| url | https://www.frontiersin.org/articles/10.3389/fchbi.2025.1576640/full |
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