7wmg

A novel chemical derivative(52) of THRB agonist

spinqualitylabelsall models 7wmg, resolution 2.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7wmg is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.93Å Ligands: 9IF 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. Publication Abstract from PubMed The design and development of agonists selectively targeting thyroid hormone receptor beta (TRbeta) and TRbeta mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound 16g, which is a potent TRbeta agonist (EC(50): 21.0 nM, 85.0% of the maximum efficacy of 1) with outstanding selectivity for TRbeta over TRalpha and also effectively activates the TRbeta(H435R) mutant. Then, we developed a highly efficient synthetic method for 16g. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. 16g also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, 16g is a well-characterized selective and mutation-sensitive TRbeta agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH). Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor beta Agonist.,Li Q, Yao B, Zhao S, Lu Z, Zhang Y, Xiang Q, Wu X, Yu H, Zhang C, Li J, Zhuang X, Wu D, Li Y, Xu Y J Med Chem. 2022 May 26;65(10):7193-7211. doi: 10.1021/acs.jmedchem.2c00144. Epub , 2022 May 4. PMID:35507418 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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