1xzx
From Proteopedia
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|PDB= 1xzx |SIZE=350|CAPTION= <scene name='initialview01'>1xzx</scene>, resolution 2.500Å | |PDB= 1xzx |SIZE=350|CAPTION= <scene name='initialview01'>1xzx</scene>, resolution 2.500Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene> | + | |LIGAND= <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=T3:3,5,3'TRIIODOTHYRONINE'>T3</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= THRB, ERBA2, NR1A2, THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= THRB, ERBA2, NR1A2, THR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1y0x|1Y0X]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1xzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xzx OCA], [http://www.ebi.ac.uk/pdbsum/1xzx PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1xzx RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190160 190160]], Thyroid hormone resistance, autosomal recessive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190160 190160]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Wagner, R.]] | [[Category: Wagner, R.]] | ||
[[Category: Webb, P.]] | [[Category: Webb, P.]] | ||
| - | [[Category: CAC]] | ||
| - | [[Category: T3]] | ||
[[Category: hormone/growth factor receptor]] | [[Category: hormone/growth factor receptor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:56:56 2008'' |
Revision as of 21:56, 30 March 2008
| |||||||
| , resolution 2.500Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | THRB, ERBA2, NR1A2, THR1 (Homo sapiens) | ||||||
| Related: | 1Y0X
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Thyroxine-Thyroid Hormone Receptor Interactions
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.
About this Structure
1XZX is a Single protein structure of sequence from Homo sapiens. 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
Page seeded by OCA on Mon Mar 31 00:56:56 2008
