Open AccessMolecular dynamics simulations of the glucocorticoid receptor DNA-binding domain suggest a role of the lever-arm mobility in transcriptional output
Author(s) -
Lautaro D. Álvarez,
Diego M. Presman,
Adalı́ Pecci
Publication year - 2017
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.0189588
Subject(s) - enhancer , transcription factor , biology , glucocorticoid receptor , transcriptional regulation , regulation of gene expression , promoter , hormone response element , gene , dna , microbiology and biotechnology , genetics , zinc finger , gene expression , computational biology , estrogen receptor , cancer , breast cancer
One of the first and essential steps in gene expression regulation involves the recruitment of transcription factors (TFs) to specific response elements located at enhancers and/or promoters of targeted genes. These DNA elements have a certain variability in both sequence and length, which may affect the final transcriptional output. The molecular mechanisms in which TFs integrate the subtle differences within specific recognition sequences to offer different transcriptional responses is still largely unknown. Here we used molecular dynamics simulations to study the DNA binding behavior of the glucocorticoid receptor (GR), a ligand-regulated TF with pleiotropic effects in almost all cells. By comparing the behavior of the wild type receptor and a well characterized Ala477Thr substitution within the rat GR DNA binding domain, we found that the region that connects the two-zinc fingers (i.e. the lever arm) would likely play a key role in GR transcriptional output.