1nq0: Difference between revisions
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|PDB= 1nq0 |SIZE=350|CAPTION= <scene name='initialview01'>1nq0</scene>, resolution 2.40Å | |PDB= 1nq0 |SIZE=350|CAPTION= <scene name='initialview01'>1nq0</scene>, resolution 2.40Å | ||
|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=4HY:[4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC+ACID'>4HY</scene> | |LIGAND= <scene name='pdbligand=4HY:[4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC+ACID'>4HY</scene>, <scene name='pdbligand=ARS:ARSENIC'>ARS</scene> | ||
|ACTIVITY= | |ACTIVITY= | ||
|GENE= THRB OR NR1A2 OR ERBA2 OR THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= THRB OR NR1A2 OR ERBA2 OR THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1nq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nq0 OCA], [http://www.ebi.ac.uk/pdbsum/1nq0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1nq0 RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==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. | 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== | ==About this Structure== | ||
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[[Category: Nguyen, H T.]] | [[Category: Nguyen, H T.]] | ||
[[Category: West, B L.]] | [[Category: West, B L.]] | ||
[[Category: thyroid hormone receptor]] | [[Category: thyroid hormone receptor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:33:55 2008'' | ||