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Designing dual inhibitors of Mdm2/MdmX: Unexpected coupling of water with gatekeeper Y100/99
Author(s) -
Lee Xiong An,
Verma Chandra,
Sim Adelene Y.L
Publication year - 2017
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25310
Subject(s) - mdmx , chemistry , structural similarity , molecular dynamics , mdm2 , residue (chemistry) , peptide , dual (grammatical number) , stereochemistry , biophysics , computational biology , biochemistry , biology , computational chemistry , philosophy , gene , linguistics
Mdm2 and MdmX share high structural similarity in their N‐terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either (i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or (ii) the dual inhibitors are agnostic to the conformation of Y100/99. The recently developed potent dual inhibitory stapled peptide Atsp7041 appears to be agnostic to the conformation of the gatekeeper residue. Proteins 2017; 85:1493–1506. © 2017 Wiley Periodicals, Inc.