Open AccessEnergetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction
Author(s) -
Kelly M. Thayer,
George A. Beyer
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0147806
Subject(s) - mdm2 , ubiquitin ligase , regulator , mutagenesis , suppressor , computational biology , ubiquitin , negative regulator , mdmx , drug discovery , chemistry , biology , microbiology and biotechnology , biophysics , mutation , biochemistry , cancer , genetics , gene , signal transduction
The ubiquitin ligase MDM2, a principle regulator of the tumor suppressor p53, plays an integral role in regulating cellular levels of p53 and thus a prominent role in current cancer research. Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive search of point mutations, resulting in the calculation of the ΔΔG comprehensive energy landscape for the p53-bound regulator. The results herein have revealed a set of residues R65-E69 on MDM2 proximal to the p53 hydrophobic binding pocket that exhibited an energetic profile deviating significantly from similar residues elsewhere in the protein. In light of the continued search for novel competitive inhibitors for MDM2, we discuss possible implications of our findings on the drug discovery field.