Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

Given the immense significance of p53 restoration for anti-cancer therapy and that p53-activating molecules are in clinical trials, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of a novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in allosteric regulation of p53, whose targeting by small molecules RITA, PpIX and licofelone blocks the binding of two p53 inhibitors, MDM2 and MDMX, thereby restoring p53 function. Deletion and mutation analysis followed by molecular modeling and its thorough validation, 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 in p53 induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators as targeted drugs. Our study provides a basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacopeia

DISTRIBUTED AUTOMATION AND CONTROL SYSTEMS

Abstract – Distributed automation and control systems are considered from the implementation point of view. The role of middleware and, in particular, the object-oriented open-standard-based CORBA is discussed and its usefulness for system integration and communication abstraction is shown on a practical example of an experimental robotic system. 1

The cross-impact of corruption and consumer culture

Purpose: The purpose of this paper is to study the relationship between corruption and consumption culture from the perspective of their mutual influence on the example of the Russian Federation. Design/methodology/approach: The research methodology was based on the use of theoretical, empirical and experimental approaches aimed at studying the mutual influence of indicators of corruption and factors that may be associated with it. Findings: The performed analysis revealed that the total number of crimes registered under corruption-related articles of the Criminal Code of the Russian Federation (Article 285 – Abuse of Power, Article 290 – Receiving a Bribe, Article 291 – Giving a Bribe) is in moderate correlation with monthly consumer spending per capita and the volume of taxes, fees and other obligatory payments to the budget. Originality/value: The practical application of the research results is possible in formation of recommendations for improving anti-corruption legislation and effective measures to prevent its causes. © 2021, Emerald Publishing Limited