Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/142381
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dc.contributor.authorKannan, Srinivasaraghavanen_US
dc.contributor.authorPartridge, Anthony Williamen_US
dc.contributor.authorLane, David P.en_US
dc.contributor.authorVerma, Chandra Shekharen_US
dc.date.accessioned2020-06-19T08:20:50Z-
dc.date.available2020-06-19T08:20:50Z-
dc.date.issued2019-
dc.identifier.citationKannan, S., Partridge, A. W., Lane, D. P., & Verma, C. S. (2019). The dual interactions of p53 with MDM2 and p300 : implications for the design of MDM2 inhibitors. International Journal of Molecular Sciences, 20(23), 5996-. doi:10.3390/ijms20235996en_US
dc.identifier.issn1661-6596en_US
dc.identifier.urihttps://hdl.handle.net/10356/142381-
dc.description.abstractProteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide ALRN_6924 that activates p53 by preventing its interaction with its negative regulator Mdm2 has entered clinical trials. This stapled peptide mimics the interaction of p53 with Mdm2. The chances that this peptide could bind to other proteins that may also interact with the Mdm2-binding region of p53 are high; one such protein is the CREB binding protein (CBP)/p300. It has been established that phosphorylated p53 is released from Mdm2 and binds to p300, orchestrating the transcriptional program. We investigate whether molecules such as ALRN_6924 would bind to p300 and, to do so, we used molecular simulations to explore the binding of ATSP_7041, which is an analogue of ALRN_6924. Our study shows that ATSP_7041 preferentially binds to Mdm2 over p300; however, upon phosphorylation, it appears to have a higher affinity for p300. This could result in attenuation of the amount of free p300 available for interacting with p53, and hence reduce its transcriptional efficacy. Our study highlights the importance of assessing off-target effects of peptide inhibitors, particularly guided by the understanding of the networks of protein-protein interactions (PPIs) that are being targeted.en_US
dc.description.sponsorshipNRF (Natl Research Foundation, S’pore)en_US
dc.description.sponsorshipASTAR (Agency for Sci., Tech. and Research, S’pore)en_US
dc.description.sponsorshipEDB (Economic Devt. Board, S’pore)en_US
dc.language.isoenen_US
dc.relation.ispartofInternational Journal of Molecular Sciencesen_US
dc.rights© 2019 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).en_US
dc.subjectScience::Biological sciencesen_US
dc.titleThe dual interactions of p53 with MDM2 and p300 : implications for the design of MDM2 inhibitorsen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.organizationBioinformatics Institute, A*STARen_US
dc.identifier.doi10.3390/ijms20235996-
dc.description.versionPublished versionen_US
dc.identifier.pmid31795143-
dc.identifier.scopus2-s2.0-85075695130-
dc.identifier.issue23en_US
dc.identifier.volume20en_US
dc.subject.keywordsStapled Peptidesen_US
dc.subject.keywordsPPIsen_US
item.fulltextWith Fulltext-
item.grantfulltextopen-
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