4lnx | pdb_00004lnx

Crystal structure of TR-alpha bound to T4 in a second site

spinqualitylabelsall models 4lnx, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4lnx is a 1 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 2.05Å Ligands: CAS, T3, T44 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease THA_HUMAN Defects in THRA are the cause of congenital hypothyroidism non-goitrous type 6 (CHNG6) [MIM:614450. A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance. Function THA_HUMAN Nuclear hormone receptor. High affinity receptor for triiodothyronine. Publication Abstract from PubMed Thyroid hormone receptors (TRs) are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many NR ligand binding domains (LBD) reveal that the ligand binds within the hydrophobic core of the ligand binding pocket (LBP), a few studies suggest the possibility of ligands bind to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10 and H11 of the TRalpha LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics (MD) simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface binding site. Extensive MD simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions. Identification of a NEW HORMONE binding site ON THE SURFACE of thyroid hormone receptor.,Souza PC, Puhl AC, Martinez L, Aparicio R, Nascimento AS, Figueira AC, Nguyen P, Webb P, Skaf MS, Polikarpov I Mol Endocrinol. 2014 Feb 19:me20131359. PMID:24552590 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thyroid hormone receptor

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