Sandbox Reserved 1105: Difference between revisions
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The TTR gene is located on chromosome 18 <ref> Wallace MR, Naylor SL, Kluve-Beckerman B, Long GL, McDonald L, Shows TB, Benson MD, Localization of the human prealbumin gene to chromosome 18 [archive], Biochem Biophys Res Commun, 1985;129:753–758</ref>. | The TTR gene is located on chromosome 18 <ref> Wallace MR, Naylor SL, Kluve-Beckerman B, Long GL, McDonald L, Shows TB, Benson MD, Localization of the human prealbumin gene to chromosome 18 [archive], Biochem Biophys Res Commun, 1985;129:753–758</ref>. | ||
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At the entry of the binding site, the TTR has a hydrophilic tail, into which the four iodine atoms of the ligand are placed. The innermost binding pocket, HBP-3, is located between the side chains of Ser 117, Thr 119, Ala 108 and Leu 110. Its surface is composed of aliphatic methyl and methylene groups, as well as the Ser 117 hydroxyl group, the carbonyl groups of Ser 117, Thr 118 and Ala 108, and the main chain NH groups of Thr 119, Ala 109 and Leu 110. The central HBP-2 is formed by the side chains of Leu 110, Ala 109, Lys 15, and Leu 17, it is primarily hydrophobic with polar or electrostatic contributions from the carbonyl groups of Lys 15, Ala 108 and Ala 109. The outermost pocket HBP-1 is located between the side chains of Ala 108, Thr 106, Met 13 and Lys 15. This pocket is lined with the methyl and methylene groups of Lys 15, Ala 108 and Thr 106 | At the entry of the binding site, the TTR has a hydrophilic tail, into which the four iodine atoms of the ligand are placed. The innermost binding pocket, HBP-3, is located between the side chains of Ser 117, Thr 119, Ala 108 and Leu 110. Its surface is composed of aliphatic methyl and methylene groups, as well as the Ser 117 hydroxyl group, the carbonyl groups of Ser 117, Thr 118 and Ala 108, and the main chain NH groups of Thr 119, Ala 109 and Leu 110. The central HBP-2 is formed by the side chains of Leu 110, Ala 109, Lys 15, and Leu 17, it is primarily hydrophobic with polar or electrostatic contributions from the carbonyl groups of Lys 15, Ala 108 and Ala 109. The outermost pocket HBP-1 is located between the side chains of Ala 108, Thr 106, Met 13 and Lys 15. This pocket is lined with the methyl and methylene groups of Lys 15, Ala 108 and Thr 106 <ref name"Klabunde">PMID:10742177</ref> (1). | ||
=== TTR-ligand complex === | === TTR-ligand complex === | ||
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==== TTR-T4 complex ===== | ==== TTR-T4 complex ===== | ||
The crystal structure of this complex is orthorhombic (4). | The crystal structure of this complex is orthorhombic (4). | ||
Two hormone binding sites are located at the dimer–dimer region bind T4 with negative cooperativity. Under physiological conditions, the bound between the natural ligand and the tetramer can’t be broken down. Moreover, there is only one hormone bound per tetramer. The negative cooperativity mechanism explain the fact that the affinity constants (Ka) for the binding of the first and the second T4 changes, they are respectively 108 and 106 M-1 | Two hormone binding sites are located at the dimer–dimer region bind T4 with negative cooperativity. Under physiological conditions, the bound between the natural ligand and the tetramer can’t be broken down. Moreover, there is only one hormone bound per tetramer. The negative cooperativity mechanism explain the fact that the affinity constants (Ka) for the binding of the first and the second T4 changes, they are respectively 108 and 106 M-1 <ref name"Klabunde">PMID:10742177</ref> (1). | ||
For the TTR-T4 complex, the HBP play a key role. The HBP interact with the four iodine groups of the thyroxine. HBPs bind the iodine of the ligands in two different ways: 3 2’ 1 1’ or 3’ 2 1 1’ with prime indicating the HBP symmetry | For the TTR-T4 complex, the HBP play a key role. The HBP interact with the four iodine groups of the thyroxine. HBPs bind the iodine of the ligands in two different ways: 3 2’ 1 1’ or 3’ 2 1 1’ with prime indicating the HBP symmetry <ref name"Klabunde">PMID:10742177</ref> (1). PICTURE | ||
A significant contribution of T4 binding to TTR comes from charged groups near the periphery of the binding site. Glu 54 and Lys15 are located near the HBP-1 pocket allowing potential electrostatic interactions with the ligands | A significant contribution of T4 binding to TTR comes from charged groups near the periphery of the binding site. Glu 54 and Lys15 are located near the HBP-1 pocket allowing potential electrostatic interactions with the ligands <ref name"Klabunde">PMID:10742177</ref> (1). | ||
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Unlike to a single DDBR, these substituted molecules make conformational change on side chains Thr119 and Ser117 with the formation of additional hydrogen bond. Furthermore, the water molecule in HBP3 pocket is displaced. | Unlike to a single DDBR, these substituted molecules make conformational change on side chains Thr119 and Ser117 with the formation of additional hydrogen bond. Furthermore, the water molecule in HBP3 pocket is displaced. | ||
<ref name="Klabunde">PMID:10742177</ref> | <ref name="Klabunde">PMID:10742177</ref> | ||
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== References == | == References == | ||
<references/> | <references/> | ||
