Structural and Drug Targeting Insights on Mutant p53.

Ana Sara Gomes,Lucília Saraiva,Alberto Inga,Emília Sousa,Helena Ramos

doi:10.3390/cancers13133344

Ana Sara Gomes, Lucília Saraiva + Show 3 more

Open Access

https://doi.org/10.3390/cancers13133344

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Abstract

Simple SummaryThe tumor suppressor protein p53 is frequently mutated in human cancers, and its reactivation represents an encouraging hope for precision anticancer therapy. Despite this, the clinical use of compounds capable of restoring the wild-type-like function to mutant p53 (mutp53) is not yet a reality. A more detailed understanding of the structural features of p53 mutations and the molecular mechanisms of mutp53 reactivators is critical to drive an efficient translation of these compounds into the clinic. In addition, this knowledge will provide insights into wild-type and mutp53 pharmacology at molecular levels, fostering the design and development of improved mutp53-targeted therapies to halt cancer.p53 is a transcription factor with a pivotal role in cell homeostasis and fate. Its impairment is a major event in tumor onset and development. In fact, about half of human cancers bear TP53 mutations that not only halt the normal function of p53, but also may acquire oncogenic gain of functions that favor tumorigenesis. Although considered undruggable for a long time, evidence has proven the capability of many compounds to restore a wild-type (wt)-like function to mutant p53 (mutp53). However, they have not reached the clinic to date. Structural studies have strongly contributed to the knowledge about p53 structure, stability, dynamics, function, and regulation. Importantly, they have afforded relevant insights into wt and mutp53 pharmacology at molecular levels, fostering the design and development of p53-targeted anticancer therapies. Herein, we provide an integrated view of mutp53 regulation, particularly focusing on mutp53 structural traits and on targeting agents capable of its reactivation, including their biological, biochemical and biophysical features. With this, we expect to pave the way for the development of improved small molecules that may advance precision cancer therapy by targeting p53.

Highlights

IntroductionRecombinant p53 proteins with specific mutations (naturally occurring alone or combined with second-site mutations that can rescue DNA binding ability) have contributed to the study of the relevance of specific amino acid residues in p53 stability and activity [23,24,25,26]
This review addresses the most relevant achievements in the functional and structural elucidation of mutp53 as well as of the mutp53-targeting agents reported to date
The classical categorization of mutp53 into contact and structural forms, and the possibility of reactivating each class by establishing extra contacts to DNA or by increasing thermal stability [95,120] seem to be inadequate based on the reported data for mutp53 reactivators

Summary

Introduction

Recombinant p53 proteins with specific mutations (naturally occurring alone or combined with second-site mutations that can rescue DNA binding ability) have contributed to the study of the relevance of specific amino acid residues in p53 stability and activity [23,24,25,26] Computational studies, such as molecular superposition and dynamics, have been used for predictive and comparison purposes in the structure-function relationship [15]. The doublet central DNA half-site A/T base pairs (positions 5 and 6) are crucial in water-mediated interactions, playing an essential role in the cooperative binding of the core dimer to its DNA half-site through minor groove hydration This interaction is directly mediated by the side chain of residue R248 (I) or indirectly via water molecules (II,III). DNA verified in cryo-EM works [17,32,33]

Dynamics and Regulation of p53

Mutant p53 Functions in Tumorigenesis

Targeting Mutant p53

Findings

Conclusions