1nq2

Two RTH Mutants with Impaired Hormone Binding

spinqualitylabelsall models 1nq2, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1nq2 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4HY, ARS, NA Gene: THRB OR NR1A2 OR ERBA2 OR THR1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [THB_HUMAN] Defects in THRB are the cause of generalized thyroid hormone resistance (GTHR) [MIM:188570]. GTHR is a disease characterized by goiter, abnormal mental functions, increased susceptibility to infections, abnormal growth and bone maturation, tachycardia and deafness. Affected individuals may also have attention deficit-hyperactivity disorders (ADHD) and language difficulties. GTHR patients also have high levels of circulating thyroid hormones (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Defects in THRB are the cause of generalized thyroid hormone resistance autosomal recessive (GTHRAR) [MIM:274300]. An autosomal recessive disorder characterized by goiter, clinical euthyroidism, end-organ unresponsiveness to thyroid hormone, abnormal growth and bone maturation, and deafness. Patients also have high levels of circulating thyroid hormones, with elevated thyroid stimulating hormone. Defects in THRB are the cause of selective pituitary thyroid hormone resistance (PRTH) [MIM:145650]; also known as familial hyperthyroidism due to inappropriate thyrotropin secretion. PRTH is a variant form of thyroid hormone resistance and is characterized by clinical hyperthyroidism, with elevated free thyroid hormones, but inappropriately normal serum TSH. Unlike GRTH, where the syndrome usually segregates with a dominant allele, the mode of inheritance in PRTH has not been established. Function [THB_HUMAN] High affinity receptor for triiodothyronine. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Resistance to hormones is commonly due to mutations in genes encoding receptors. Resistance to thyroid hormone is due mostly to mutations of the beta-form of the human (h) thyroid hormone receptor (hTRbeta). We determined x-ray crystal structures of two hTRbeta ligand-binding domains (LBDs), Ala 317 Thr and Arg 316 His. Amino acids 316 and 317 form part of the hormone-binding pocket. The methyl of Ala 317, contacting iodine, sculpts the T3 hormone-binding pocket. Arg 316 is not in direct contact with T3 and has an unknown role in function. Remarkably, the Arg forms part of an unusual buried polar cluster in hTRbeta. Although the identity of the amino acids changes, the polar cluster appears in all nuclear receptors. In spite of the differing roles of 316 and 317, both resistance to thyroid hormone mutants display decreased T3 affinity and weakened transcriptional activation. The two mutants differ in that the Arg 316 His receptor does not form TR-TR homodimers on DNA. 3,5,3'-Triiodothyroacetic acid is bound to both receptors. Thr 317 repositions 3,5,3'-triiodothyroacetic acid distending the face of the receptor that binds coregulators. Arg 316 forms two hydrogen bonds with helix 1. Both are lost with mutation to His displacing helix 1 of the LBD and disordering the loop after helix 1. The stability of the helix 1, deriving in part from the buried polar cluster, is important for hormone binding and formation of TR dimers. The observation that the Arg 316 His mutation affects these functions implies a role for helix 1 in linking hormone binding to the DNA-binding domain-LBD configuration. Two resistance to thyroid hormone mutants with impaired hormone binding.,Huber BR, Sandler B, West BL, Cunha Lima ST, Nguyen HT, Apriletti JW, Baxter JD, Fletterick RJ Mol Endocrinol. 2003 Apr;17(4):643-52. Epub 2003 Jan 16. PMID:12554782 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thyroid hormone receptor

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