Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket

Abstract

The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects. Inspired by the hypothesis that structural changes that are associated with events initiating unfolding in DBD are likely to present opportunities for inhibition, we investigate the dynamics of the wild type (WT) and some aggregating mutants through extensive all atom explicit solvent MD simulations. Simulations reveal differential conformational sampling between the WT and the mutants of a turn region (S6–S7) that is contiguous to a known aggregation-prone region (APR). The conformational properties of the S6–S7 turn appear to be modulated by a network of interacting residues. We speculate that changes that take place in this network as a result of the mutational stress result in the events that destabilize the DBD and initiate unfolding. These perturbations also result in the emergence of a novel pocket that appears to have druggable characteristics. FDA approved drugs are computationally screened against this pocket.

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

“…Recent simulations suggest that a subset of mutations could lead to the formation of a druggable binding pocket, potentially opening therapeutic options to restore p53 function [92]. TP53 mutant patients had significantly worse OS in the patient subgroups treated only with endocrine therapy, or no systemic treatment at all ( Figure 5).…”

Markov state models and NMR uncover an overlooked allosteric loop in p53

“…Using this methodology we arrived at a final number of 24 pairs Figure 1a) and recessed conformations [46][47][48] Since the tICs are ordered in terms of slowest to fastest motions, the correspondence of L6 anchor features with the first of the components indicates that transitions involving loop L6 are slower than those for loop L1. To further check the importance of these loops in the relevant motions of the protein, we performed additional tICA analysis specifically incorporating other motifs known to play significant roles in p53 function: helices H1 and H2 and loops L2 and L3, which together with L1 make up the DNA interaction surface, and loop S6/7, recently identified as a flexible region in p53 mutants 52 (Figure 1a).…”

Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53

“…Combined molecular dynamics (MD)/experimental studies of R175H [42] and Y220C [43,44] DBD found evidence for previously hidden subpockets, the latter of which were useful in the aforementioned affinity optimizations. More recently, MD simulations of WT DBD and the stabilityclass V143A mutant found differences in the turn region between two beta strands (residues 208-213) [45]. The turn adopts an 'open' conformation in V143A that the authors hypothesized could be The affinity of Y220C cavity binders has progressively improved in recent years.…”