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Title of article :
Molecular Dynamics Studies of a Molecular Switch in the Glucocorticoid Receptor
Author/Authors :
Thomas Stockner، نويسنده , , Heinz Sterk، نويسنده , , Robert Kaptein، نويسنده , , Alexandre MJJ Bonvin، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2003
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Abstract :
The glucocorticoid receptor (GR) is a hormone dependent nuclear receptor that regulates gene transcription when bound to the glucocorticoid response element (GRE). The GRE acts as an allosteric effector, inducing a structural change in the GR DNA-binding domain (GR DBD) upon binding, thereby switching the GR to an active conformation. A similar conformational change can be induced by two single point mutations: Ser459Ala and Pro493Arg. Structural and dynamical aspects of the conformational switch have been investigated by molecular dynamics simulations. Our results indicate that these two mutants, which share a similar phenotype, exert their action at a structural level through different mechanisms. In the Arg493 mutant, the D-loop and the second helix are stabilized in a conformation that preforms the protein–protein dimer interface. In the Ala459 mutant, the structurally important hydrogen bond between Arg496 and Ser459 is missing, which leads to a core reorganization and a reorientation of the second helical region. Although remote, both in sequence and three dimensional structure, these two mutations induce structural changes that are ultimately reflected in similar regions of the GR DBD structure, namely the D-loop and the short second helical region. These correspond to hot area of the GR DBD that are important both for DNA-binding and for the proper formation of the protein–protein interface. The conformational rearrangements in these area are proposed to decrease unfavorable protein–DNA and protein–protein contacts and allow unspecific DNA-binding leading to the squelching phenotype of the mutants. The GR DBD can thus exist in two states, a transcriptionally active and an inactive state. Switching between these states can be accomplished either by GRE binding or by the described mutations.
Keywords :
Glucocorticoid receptor , mutations , Molecular dynamics , specific and unspecific DNA binding , GROMOS96
Journal title :
Journal of Molecular Biology
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