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PDBsum entry 1nq0
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Hormone/growth factor receptor
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PDB id
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1nq0
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Thyroid hormone receptor-Beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the n-Terminal ligand-Binding domain.
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Authors
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B.R.Huber,
M.Desclozeaux,
B.L.West,
S.T.Cunha-Lima,
H.T.Nguyen,
J.D.Baxter,
H.A.Ingraham,
R.J.Fletterick.
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Ref.
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Mol Endocrinol, 2003,
17,
107-116.
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PubMed id
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Abstract
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Resistance to thyroid hormone (RTH) syndrome is associated with mutations in the
human thyroid hormone receptor-beta (hTRbeta), many of which show marked
reduction in hormone binding. Here, we investigated the structural consequences
of two RTH mutants (A234T and R243Q), residing in the flexible N-terminal
portion of the ligand binding domain (LBD), which exhibit modestly reduced
hormone binding with impaired release of corepressor. X-ray crystallography
analyses revealed that these two RTH mutants modulate the position of this
flexible region by either altering the movement of helix 1 (A234T) or disrupting
a salt bridge (R243Q). The subsequent increased flexibility and mobility in
regions after the two sites of mutation coincided with a disorganized LBD.
Consistent with this finding, the ability of these mutant N-terminal regions
(234-260) to recruit the remaining LBD was decreased in a ligand-dependent helix
assembly assay. Collectively, these data suggest that structural information
imparted by the flexible segment in the N-terminal LBD is critical for overall
stability of the LBD. Thus, these structural analyses provide mechanistic
insight into the etiology of RTH disease in human TRbeta mutants that exhibit
hormone binding with decreased ligand-dependent corepressor release.
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