1q4x
From Proteopedia
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|PDB= 1q4x |SIZE=350|CAPTION= <scene name='initialview01'>1q4x</scene>, resolution 2.8Å | |PDB= 1q4x |SIZE=350|CAPTION= <scene name='initialview01'>1q4x</scene>, resolution 2.8Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=G24:[4-(3-BENZYL-4-HYDROXYBENZYL)-3,5-DIMETHYLPHENOXY]ACETIC ACID'>G24</scene> | + | |LIGAND= <scene name='pdbligand=G24:[4-(3-BENZYL-4-HYDROXYBENZYL)-3,5-DIMETHYLPHENOXY]ACETIC+ACID'>G24</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=1q4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q4x OCA], [http://www.ebi.ac.uk/pdbsum/1q4x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1q4x RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor beta. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3' position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor beta at 2.8-A resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 A in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components. | Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor beta. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3' position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor beta at 2.8-A resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 A in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components. | ||
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| - | ==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: Togashi, M.]] | [[Category: Togashi, M.]] | ||
[[Category: Webb, P.]] | [[Category: Webb, P.]] | ||
| - | [[Category: G24]] | ||
[[Category: conformational change in two framework helices upon ligand binding]] | [[Category: conformational change in two framework helices upon ligand binding]] | ||
| - | ''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 23:08:52 2008'' |
Revision as of 20:08, 30 March 2008
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| , resolution 2.8Å | |||||||
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| Ligands: | |||||||
| Gene: | THRB OR NR1A2 OR ERBA2 OR THR1 (Homo sapiens) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Human Thyroid Hormone Receptor beta LBD in complex with specific agonist GC-24
Overview
Selective therapeutics for nuclear receptors would revolutionize treatment for endocrine disease. Specific control of nuclear receptor activity is challenging because the internal cavities that bind hormones can be virtually identical. Only one highly selective hormone analog is known for the thyroid receptor, GC-24, an agonist for human thyroid hormone receptor beta. The compound differs from natural hormone in benzyl, substituting for an iodine atom in the 3' position. The benzyl is too large to fit into the enclosed pocket of the receptor. The crystal structure of human thyroid hormone receptor beta at 2.8-A resolution with GC-24 bound explains its agonist activity and unique isoform specificity. The benzyl of GC-24 is accommodated through shifts of 3-4 A in two helices. These helices are required for binding hormone and positioning the critical helix 12 at the C terminus. Despite these changes, the complex associates with coactivator as tightly as human thyroid hormone receptor bound to thyroid hormone and is fully active. Our data suggest that increased specificity of ligand recognition derives from creating a new hydrophobic cluster with ligand and protein components.
About this Structure
1Q4X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor., Borngraeber S, Budny MJ, Chiellini G, Cunha-Lima ST, Togashi M, Webb P, Baxter JD, Scanlan TS, Fletterick RJ, Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15358-63. Epub 2003 Dec 12. PMID:14673100
Page seeded by OCA on Sun Mar 30 23:08:52 2008
