Sandbox Reserved 1105: Difference between revisions

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The channel has three sets of small hydrophobic depressions, termed halogen binding pockets (HBPs). But then, when the side chain of the TTR changes of conformation, these pockets can realise more hydrogen bonds with other molecules, they can be donor or acceptor.  Thus, they had this name due to their ability to bind the iodines of thyroxine (T4) its natural ligand <ref name="Labaudinière">Labaudinière R. Chapter 9 Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy. Orphan Drugs and Rare Diseases. Aug 2014 202-229. DOI:https://doi.org/10.1039/9781782624202-00202</ref>.
The channel has three sets of small hydrophobic depressions, termed halogen binding pockets (HBPs). But then, when the side chain of the TTR changes of conformation, these pockets can realise more hydrogen bonds with other molecules, they can be donor or acceptor.  Thus, they had this name due to their ability to bind the iodines of thyroxine (T4) its natural ligand <ref name="Labaudinière">Labaudinière R. Chapter 9 Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy. Orphan Drugs and Rare Diseases. Aug 2014 202-229. DOI:https://doi.org/10.1039/9781782624202-00202</ref>.
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 dimer interface of the TTR is divided in two part, the inner and the outer binding cavity. 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>.
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 dimer interface of the TTR is divided in two part, the inner and the outer binding cavity. 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>.




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And Phe64 is in van der Waals contact with Cys10 via Pro11 in monomer A. Each monomer contain a single cysteine (Cys10), which is usually bound to various sulfhydryls or sulfite from plasma. S-oxidation of Cys10 to cysteic acid has a stabilizing effect on the monomer. It may be derived from hydrogen bonds between the sulfonic oxygens of Cys10–SO3 – and Gly57 N, His56 NE and Arg104 NH1 <ref name= "Altland"> Altland, K., Benson, M. D., Costello, C. E., Ferlini, A., Hazenberg, B. P. C., Hund, E., … Winter, P. (2007). Genetic microheterogeneity of human transthyretin detected by IEF. ELECTROPHORESIS, 28(12), 2053–2064. doi: http://dx.doi.org/10.1002/elps.200600840</ref>.
And Phe64 is in van der Waals contact with Cys10 via Pro11 in monomer A. Each monomer contain a single cysteine (Cys10), which is usually bound to various sulfhydryls or sulfite from plasma. S-oxidation of Cys10 to cysteic acid has a stabilizing effect on the monomer. It may be derived from hydrogen bonds between the sulfonic oxygens of Cys10–SO3 – and Gly57 N, His56 NE and Arg104 NH1 <ref name= "Altland"> Altland, K., Benson, M. D., Costello, C. E., Ferlini, A., Hazenberg, B. P. C., Hund, E., … Winter, P. (2007). Genetic microheterogeneity of human transthyretin detected by IEF. ELECTROPHORESIS, 28(12), 2053–2064. doi: http://dx.doi.org/10.1002/elps.200600840</ref>.
Monomers of TTR will be called A, B, C, D. And as we consider the TTR as a dimer of dimer, we have A and B the upper part of the protein and C and D the lower part. The contact between upper and lower dimers is made via β-sheet contacts, creating hydrogen bonds between main-chain atoms. In contrast to the monomer associations, contacts between the upper and lower parts are much less important so that the dimer assembly unit of TTR is best defined as the monomers which are joined by β-strand hydrogen bonding. Two funnel-shaped hormone binding sites are located at the dimer–dimer region.
Monomers of TTR will be called A, B, AA, BA. And as we consider the TTR as a dimer of dimer, we have A and AA the upper part of the protein and B and BA the lower part. The contact between upper and lower dimers is made via β-sheet contacts, creating hydrogen bonds between main-chain atoms. In contrast to the monomer associations, contacts between the upper and lower parts are much less important so that the dimer assembly unit of TTR is best defined as the monomers which are joined by β-strand hydrogen bonding. Two funnel-shaped hormone binding sites are located at the dimer–dimer region.




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