1q4x
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Selective therapeutics for nuclear receptors would revolutionize treatment | + | 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. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Baxter, J | + | [[Category: Baxter, J D.]] |
[[Category: Borngraeber, S.]] | [[Category: Borngraeber, S.]] | ||
| - | [[Category: Budny, M | + | [[Category: Budny, M J.]] |
[[Category: Chiellini, G.]] | [[Category: Chiellini, G.]] | ||
| - | [[Category: Cunha-Lima, S | + | [[Category: Cunha-Lima, S T.]] |
| - | [[Category: Fletterick, R | + | [[Category: Fletterick, R J.]] |
| - | [[Category: Scanlan, T | + | [[Category: Scanlan, T S.]] |
[[Category: Togashi, M.]] | [[Category: Togashi, M.]] | ||
[[Category: Webb, P.]] | [[Category: Webb, P.]] | ||
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[[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 Thu Feb 21 14:35:53 2008'' |
Revision as of 12:35, 21 February 2008
|
Crystal Structure of Human Thyroid Hormone Receptor beta LBD in complex with specific agonist GC-24
Contents |
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.
Disease
Known diseases associated with this structure: Thyroid hormone resistance OMIM:[190160], Thyroid hormone resistance, autosomal recessive OMIM:[190160]
About this Structure
1Q4X is a Single protein structure of sequence from Homo sapiens with as ligand. 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 Thu Feb 21 14:35:53 2008
