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Nanosensing protein allostery using a bivalent mouse double minute two (MDM2) assay

Robson, Anna F. and Hupp, Ted R. and Lickiss, Fiona and Ball, Kathryn L. and Faulds, Karen and Graham, Duncan (2012) Nanosensing protein allostery using a bivalent mouse double minute two (MDM2) assay. Proceedings of the National Academy of Sciences, 109 (21). pp. 8073-8078. ISSN 0027-8424

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Abstract

The tumor suppressor protein, p53, is either mutated or absent in >50% of cancers and is negatively regulated by the mouse double minute (MDM2) protein. Understanding and inhibition of the MDM2-p53 interaction are, therefore, critical for developing novel chemotherapeutics, which are currently limited because of a lack of appropriate study tools. We present a nanosensing approach to investigate full-length MDM2 interactions with p53, thus providing an allosteric assay for identifying binding ligands. Surface-enhanced Raman scattering (SERS)-active nanoparticles, functionalized with a p53 peptide mimic (peptide 12.1), display biologically specific aggregation following addition of MDM2. Nanoparticle assembly is competitively inhibited by the N-terminal MDM2-binding ligands peptide 12.1 and Nutlin-3. This study reports nanoparticle assembly through specific protein-peptide interactions that can be followed by SERS. We demonstrate solution-based MDM2 allosteric interaction studies that use the full-length protein.