1xzx
From Proteopedia
(New page: 200px<br /> <applet load="1xzx" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xzx, resolution 2.500Å" /> '''Thyroxine-Thyroid ...) |
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| - | [[Image:1xzx.gif|left|200px]]<br /> | + | [[Image:1xzx.gif|left|200px]]<br /><applet load="1xzx" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1xzx, resolution 2.500Å" /> | caption="1xzx, resolution 2.500Å" /> | ||
'''Thyroxine-Thyroid Hormone Receptor Interactions'''<br /> | '''Thyroxine-Thyroid Hormone Receptor Interactions'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha | + | Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha and beta) that bind triiodothyronine (T(3), 3,5,3'-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T(4), 3,5,3',5'-tetraiodo-l-thyronine) with lower affinity. T(4) contains a bulky 5' iodine group absent from T(3). Because T(3) is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5' substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T(4) affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T(4) complexes adopt a conformation that differs from TR-T(3) complexes in solution. Nonetheless, T(4) behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T(3) does not contribute to agonist activity. We determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.1-A resolution. Comparison of the structures reveals that TRbeta accommodates T(4) through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5' iodine and complete the coactivator binding surface. While T(3) is the major active TH, our results suggest that T(4) could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5' extension should be considered in TR ligand design. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XZX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CAC and T3 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1XZX is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CAC:'>CAC</scene> and <scene name='pdbligand=T3:'>T3</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XZX OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Apriletti, J | + | [[Category: Apriletti, J W.]] |
| - | [[Category: Baxter, J | + | [[Category: Baxter, J D.]] |
| - | [[Category: Fletterick, R | + | [[Category: Fletterick, R J.]] |
| - | [[Category: Huber, B | + | [[Category: Huber, B R.]] |
[[Category: Juric, S.]] | [[Category: Juric, S.]] | ||
| - | [[Category: Lima, S | + | [[Category: Lima, S T.Cunha.]] |
[[Category: Nilsson, S.]] | [[Category: Nilsson, S.]] | ||
[[Category: Sandler, B.]] | [[Category: Sandler, B.]] | ||
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[[Category: hormone/growth factor receptor]] | [[Category: hormone/growth factor receptor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:00:23 2008'' |
Revision as of 14:00, 21 February 2008
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Thyroxine-Thyroid Hormone Receptor Interactions
Contents |
Overview
Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha and beta) that bind triiodothyronine (T(3), 3,5,3'-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T(4), 3,5,3',5'-tetraiodo-l-thyronine) with lower affinity. T(4) contains a bulky 5' iodine group absent from T(3). Because T(3) is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5' substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T(4) affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T(4) complexes adopt a conformation that differs from TR-T(3) complexes in solution. Nonetheless, T(4) behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T(3) does not contribute to agonist activity. We determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.1-A resolution. Comparison of the structures reveals that TRbeta accommodates T(4) through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5' iodine and complete the coactivator binding surface. While T(3) is the major active TH, our results suggest that T(4) could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5' extension should be considered in TR ligand design.
Disease
Known diseases associated with this structure: Thyroid hormone resistance OMIM:[190160], Thyroid hormone resistance, autosomal recessive OMIM:[190160]
About this Structure
1XZX is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Thyroxine-thyroid hormone receptor interactions., Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JD, J Biol Chem. 2004 Dec 31;279(53):55801-8. Epub 2004 Oct 4. PMID:15466465
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