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PDBsum entry 3g6t
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Transcription/DNA
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PDB id
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3g6t
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References listed in PDB file
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Key reference
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Title
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Dna binding site sequence directs glucocorticoid receptor structure and activity.
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Authors
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S.H.Meijsing,
M.A.Pufall,
A.Y.So,
D.L.Bates,
L.Chen,
K.R.Yamamoto.
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Ref.
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Science, 2009,
324,
407-410.
[DOI no: ]
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PubMed id
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Abstract
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Genes are not simply turned on or off, but instead their expression is
fine-tuned to meet the needs of a cell. How genes are modulated so precisely is
not well understood. The glucocorticoid receptor (GR) regulates target genes by
associating with specific DNA binding sites, the sequences of which differ
between genes. Traditionally, these binding sites have been viewed only as
docking sites. Using structural, biochemical, and cell-based assays, we show
that GR binding sequences, differing by as little as a single base pair,
differentially affect GR conformation and regulatory activity. We therefore
propose that DNA is a sequence-specific allosteric ligand of GR that tailors the
activity of the receptor toward specific target genes.
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Figure 2.
Fig. 2. DNA sequence-mediated structural differences in GR-DBD.
(A) Domain structure of GR.  [1], tau1. (B)
Overlay of chains A and B from GR-DBD:Pal complex shows packed
and flipped conformations. (C) Overlay of chain B from GR-DBD
complexed with 4-bp spacer (15) (magenta) and 3-bp spacer GBS
(green). (D) Composite omit maps of GR-DBD complexed with
different GBSs (GilZ, FKBP5, Sgk, and Pal) under the same
conditions. Lever arm peptide is shown with 2Fo-Fc (black mesh)
and composite omit map (red mesh) overlaid.
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Figure 4.
Fig. 4. Receptor activity is modulated by lever arm residues.
(A) H472 is critical for tuning activity. Effects of mutating
lever arm residues were assayed using GBS reporters; activities
are plotted as percentage of wild type ± SEM (n  3).
(B) H472 resides in the DBD pocket formed by the carbonyl
adjacent to V468, Y497, and L501. (C) Human DBD sequence
alignments reveal variation at V468, Y497, and L501.
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The above figures are
reprinted
from an Open Access publication published by the AAAs:
Science
(2009,
324,
407-410)
copyright 2009.
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