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Thyroid hormone conformations

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... [Pg.35]

A similar approach was used toward the identification of antagonists of the thyroid hormone receptor [265]. Again, a model of this receptor in its predicted antagonist-bound conformation served to select 100 antagonist candidates out of a library of 250000 compounds. Fourteen of 75 tested molecules were found to antagonize this... [Pg.95]

Figure 2 Nuclear hormone receptor structure and ligands, (a) The functional domains of nuclear hormone receptors. They act as either homodimers or heterodimers with a ligand binding domain and a DNA binding domain that are separated by a linker sequence, (b) The conformational change in helix 12 when ligand binding occurs (61, 62). All-trans retinoic acid is shown behind helix 12. (c) Examples of synthetic ligands for estrogen receptor (SERMs) and thyroid hormone receptor (Thyromimetics). Figure 2 Nuclear hormone receptor structure and ligands, (a) The functional domains of nuclear hormone receptors. They act as either homodimers or heterodimers with a ligand binding domain and a DNA binding domain that are separated by a linker sequence, (b) The conformational change in helix 12 when ligand binding occurs (61, 62). All-trans retinoic acid is shown behind helix 12. (c) Examples of synthetic ligands for estrogen receptor (SERMs) and thyroid hormone receptor (Thyromimetics).
The thyroid hormones, exemplified by thyroxine (5), provide an example of the use of both line-shape analysis and NMR relaxation time measurements, to give an insight into the internal flexibility, and perhaps the mode of action, of pharmaceutically important molecules (52,53,58). The thyroid hormones act by binding to a nuclear receptor and appear to control receptor function by inducing a conformational change that directs the alignment of functionally critical secondary-structure elements of the receptor (59). Synthetic thyrox-... [Pg.529]

In this model, both aromatic rings of the thyroid hormones jump rapidly between two energetically equivalent conformations on a... [Pg.530]

Ikeda, M., Wilcox, E. C., and Chin, W. W. (1996). Different DNA elements can modulate the conformation of thyroid hormone receptor heterodimer and its transcription activity,. Biol Chm. 271, 23096-23104. [Pg.682]

Thyroid Hormones-Receptor Interactions Binding Models from Molecular Conformation and Binding Affinity Data... [Pg.277]

Figure L Principal thyroid hormones thyroxine (Th) and triiodothyronine (Ts) showing their molecular conformation and numbering scheme... Figure L Principal thyroid hormones thyroxine (Th) and triiodothyronine (Ts) showing their molecular conformation and numbering scheme...
Figure 5. Thyroid hormones illustrating transoid and cisoid overall conformation... Figure 5. Thyroid hormones illustrating transoid and cisoid overall conformation...
Figure 6. Plot of the torsion angle (C5-C4-041-C1 ) and (C4-041-C1 -C6) for those thyroactive crystal structures listed in Ref. 11. Diphenylether conformation for all thyroid hormones. Figure 6. Plot of the torsion angle <f> (C5-C4-041-C1 ) and <f> (C4-041-C1 -C6) for those thyroactive crystal structures listed in Ref. 11. Diphenylether conformation for all thyroid hormones.
Analysis of the TBPA-Ti complex (39,40) indicates that the binding site for the hormone is located deep inside the channel. The hormone makes extensive interactions with the protein side chains that project into the channel. The 4 -hydroxyl of Ti interacts with a patch of hydroxy-amino acids of the protein while each of the iodines makes contact with a number of hydro-phobic protein residues. The T amino acid side chain functional groups are in appropriate positions to interact with glutamic acid and lysine residues. Thus, this channel provides a favorable environment for each of the characteristic substituents of the thyroid hormone (40). However, because of the Ti orientation disorder in the protein complex, this structural model is not a sensitive measure of the observed correlations between diphenyl ether conformations and binding affinity data. [Pg.293]

Therefore, changes in the relative binding affinities of thyroid hormone structures to receptors will ultimately depend upon the specific steric requirements of the binding site and the ability of the hormones to adopt the required conformation. [Pg.293]

The interaction between free thyroid hormones and their binding proteins (TBPs) conforms to a reversible binding equilibrium that is described by the following mass action relationship ... [Pg.2073]

Structure of 3,3, 5,5 -tetraiodo-L-thyronine (T4). T4 is a substituted tyrosine or a diphenylether derivative of alanine. Positions in the outer phenolic ring have prime designations, in contrast to those in the inner ring. T4 is iodinated at positions 3 and 5 in both rings. [Modified and reproduced with permission from V. Cody, Thyroid hormone interactions molecular conformation, protein binding, and hormone action. Endocr. Rev. 1,140 (1980). (c)1980by the Endocrine Society.]... [Pg.770]

Binding of thyroid hormone tri ers a conformational change in the receptor converting it to a transcriptional activator. [Pg.416]


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See also in sourсe #XX -- [ Pg.929 , Pg.930 ]




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