RT Journal Article SR Electronic T1 Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy JF bioRxiv FD Cold Spring Harbor Laboratory SP 384248 DO 10.1101/384248 A1 Joanna Zawacka-Pankau A1 Vera V. Grinkevich A1 Mikhail Burmakin A1 Aparna Vema A1 Karin Fawkner A1 Natalia Issaeva A1 Virginia Andreotti A1 Eleanor R. Dickinson A1 Elisabeth Hedström A1 Clemens Spinnler A1 Alberto Inga A1 Lars-Gunnar Larsson A1 Anders Karlén A1 Olga Tarasova A1 Vladimir Poroikov A1 Sergey Lavrenov A1 Maria Preobrazhenskaya A1 Perdita E. Barran A1 Andrei L. Okorokov A1 Galina Selivanova YR 2018 UL http://biorxiv.org/content/early/2018/12/07/384248.abstract AB Given the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.