1nq1
From Proteopedia
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'''TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the Nterminal LBD''' | '''TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the Nterminal LBD''' | ||
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[[Category: Nguyen, H T.]] | [[Category: Nguyen, H T.]] | ||
[[Category: West, B L.]] | [[Category: West, B L.]] | ||
| - | [[Category: | + | [[Category: Alpha helical]] |
| - | [[Category: | + | [[Category: Ligand binding domain]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:50:35 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 23:50, 2 May 2008
TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the Nterminal LBD
Overview
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.
About this Structure
1NQ1 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain., Huber BR, Desclozeaux M, West BL, Cunha-Lima ST, Nguyen HT, Baxter JD, Ingraham HA, Fletterick RJ, Mol Endocrinol. 2003 Jan;17(1):107-16. PMID:12511610 Page seeded by OCA on Sat May 3 02:50:35 2008
