Liothyronine(T3)

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Revision as of 06:05, 24 October 2008

Liothyronine(T3)

Pubchem(5920)

A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5' position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly T3.

KEGG Pathway(C02465) Tyrosine metabolism Neuroactive ligand-receptor interaction Autoimmune thyroid disease Comment Thyroid hormone More active than T4

MMDB ID: 10776 PDB ID: 1BSX Reference: Darimont BD, Wagner RL, Apriletti JW, Stallcup MR, Kushner PJ, Baxter JD, Fletterick RJ, Yamamoto KRStructure and specificity of nuclear receptor-coactivator interactionsGenes Dev. v12, p.3343-3356 Combinatorial regulation of transcription implies flexible yet precise assembly of multiprotein regulatory complexes in response to signals. Biochemical and crystallographic analyses revealed that hormone binding leads to the formation of a hydrophobic groove within the ligand binding domain (LBD) of the thyroid hormone receptor that interacts with an LxxLL motif-containing alpha-helix from GRIP1, a coactivator....

MMDB ID: 28583 PDB ID: 1SN5 Reference: Eneqvist T, Lundberg E, Karlsson A, Huang S, Santos CR, Power DM, Sauer-Eriksson AEHigh resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxineJ. Biol. Chem. v279, p.26411-26416 Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid hormones and vitamin A. So far, TTR has only been found in vertebrates, of which piscine TTR displays the lowest sequence identity with human TTR (47%). Human and piscine TTR bind both thyroid hormones 3,5,3"-triiodo-l-thyronine (T(3)) and 3,5,3",5"-tetraiodo-l-thyronine (thyroxine, T(4))..

MMDB ID: 31718 PDB ID: 1XZX Reference: Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, Cunha Lima ST, Juric S, Nilsson S, Wagner R, Fletterick RJ, Baxter JDThyroxine-thyroid hormone receptor interactionsJ. Biol. Chem. v279, p.55801-55808 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....

MMDB ID: 40533 PDB ID: 2H6W

MMDB ID: 40534 PDB ID: 2H77

MMDB ID: 40535 PDB ID: 2H79

Reference: Nascimento AS, Dias SM, Nunes FM, Aparicio R, Ambrosio AL, Bleicher L, Figueira AC, Santos MA, de Oliveira Ne, Fischer H, Togashi M, Craievich AF, Garratt RC, Baxter JD, Webb P, Polikarpov IStructural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor functionJ. Mol. Biol. v360, p.586-598 The thyroid hormone receptor (TR) D-domain links the ligand-binding domain (LBD, EF-domain) to the DNA-binding domain (DBD, C-domain), but its structure, and even its existence as a functional unit, are controversial. The D domain is poorly conserved throughout the nuclear receptor family and was originally proposed to comprise an unfolded hinge that facilitates rotation between the LBD and the DBD....

MMDB ID: 59297 PDB ID: 2PIV

MMDB ID: 59298 PDB ID: 2PIW

Reference: Estebanez-Perpina E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJA surface on the androgen receptor that allosterically regulates coactivator bindingProc. Natl. Acad. Sci. U. S. A. v104, p.16074-16079 Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor"s binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops....

Physical Property Value Units Temp (deg C) Source Melting Point 236.5 dec deg C EXP log P (octanol-water) 2.960 (none) EST Water Solubility 3.96 mg/L 37 EXP Vapor Pressure 3.90E-16 mm Hg 25 EST Henry's Law Constant 3.41E-18 atm-m3/mole 25 EST Atmospheric OH Rate Constant 4.82E-11 cm3/molecule-sec 25 EST

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source rat LDLo oral 7500mg/kg (7500mg/kg) Roczniki Panstwowego Zakladu Higieny. Vol. 32, Pg. 197, 1981.

Reference1 Nature Chemical Biology 4, 548 - 556 (2008) Published online: 10 August 2008 | doi:10.1038/nchembio.106

Cytosporone B is an agonist for nuclear orphan receptor Nur77

Yanyan Zhan1,3, Xiping Du1,3, Hangzi Chen1, Jingjing Liu1, Bixing Zhao1, Danhong Huang1, Guideng Li1, Qingyan Xu1, Mingqing Zhang1, Bart C Weimer2, Dong Chen2, Zhe Cheng1, Lianru Zhang1, Qinxi Li1, Shaowei Li1, Zhonghui Zheng1, Siyang Song1, Yaojian Huang1, Zhiyun Ye1, Wenjin Su1, Sheng-Cai Lin1, Yuemao Shen1 & Qiao Wu1

Abstract

Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B–dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.