Grinkevich, Vera V;
Vema, Aparna;
Fawkner, Karin;
Issaeva, Natalia;
Andreotti, Virginia;
Dickinson, Eleanor R;
Hedström, Elisabeth;
... Zawacka-Pankau, Joanna E; + view all
(2022)
Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule.
Frontiers in Molecular Biosciences
, 9
, Article 823195. 10.3389/fmolb.2022.823195.
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Abstract
Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.
| Type: | Article |
|---|---|
| Title: | Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fmolb.2022.823195 |
| Publisher version: | https://doi.org/10.3389/fmolb.2022.823195 |
| Language: | English |
| Additional information: | Copyright © 2022 Grinkevich, Vema, Fawkner, Issaeva, Andreotti, Dickinson, Hedström, Spinnler, Inga, Larsson, Karlén, Wilhelm, Barran, Okorokov, Selivanova and Zawacka-Pankau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | p53, N-terminus, allosteric inhibition, MDMX(4), MDM2 |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10150492 |
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