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

Proceedings of the National Academy of Sciences of the United States of America
Anna F RobsonDuncan Graham

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.

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Citations

Oct 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·Michal BistaAlan R Fersht
Nov 15, 2012·Genes & Cancer·Anand PonnuswamyRobin Fåhraeus
Feb 19, 2013·Trends in Biotechnology·Marc VendrellYoung-Tae Chang
Dec 23, 2015·Chemical Society Reviews·Stacey LaingKaren Faulds
Jan 16, 2013·Physical Chemistry Chemical Physics : PCCP·Mhairi M HarperKaren Faulds
May 14, 2021·Scientific Reports·Sharon Min Qi CheeFarid J Ghadessy
Nov 5, 2021·Chemical Communications : Chem Comm·Sian Sloan-DennisonKaren Faulds

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