Sandbox Reserved 1105: Difference between revisions

=== Structure ===

Human TTR is a 54 kDa homo-tetramer, described as a dimer of dimer, rich in β-sheet. It is composed of 127 amino acids assembled around the central channel of the protein, resulting in a 222 symmetry protein. This tetramer contains a channel divided into two symmetry-related L-T4-binding sites.   

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 outermost pockets <scene name='82/829358/Hbp1/3'>HBP1</scene> and <scene name='82/829358/Hbp1prim/3'>HBP1'</scene> are located between the side chains of <scene name='82/829358/Hbp1aa/1'>Ala 108, Thr 106, Met 13 and Lys 15</scene> <ref name= "Klabunde">PMID: 10742177</ref>. The central <scene name='82/829358/Hbp2/2'>HBP2</scene> and <scene name='82/829358/Hbp2prime/1'>HBP2'</scene> are formed by the side chains of <scene name='82/829358/Hbp2aa/1'>Leu 110, Ala 109, Lys 15, and Leu 17</scene>, it is primarily hydrophobic with polar or electrostatic contributions from the carbonyl groups of Lys 15, Ala 108 and Ala 109. The innermost binding pockets, <scene name='82/829358/Hbp3/3'>HBP3</scene> and <scene name='82/829358/Hbp3prim/2'>HBP3'</scene>, are located between the side chains of <scene name='82/829358/Hbp3aa/2'>Ser 117, Thr 119, Ala 108 and Leu 110</scene>. Their surfaces are 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.  

Each monomer is composed of an <scene name='82/829358/Helix/1'>α-helix</scene> and <scene name='82/829358/Sheet/1'>two four stranded β-sheets</scene>, which results in two eight-stranded β-sheets per dimer <ref name="seb">Sebastião, M. P., Lamzin, V., Saraiva, M. J., & Damas, A. M. (2001). Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution. Journal of Molecular Biology, 306(4), 733–744. doi:http://dx.doi.org/10.1006/jmbi.2000.4415  </ref>. There is a large solvent channel which passes between the two sheets in which two molecules of T4 can bind. Monomers associate via the formation of an eight-stranded anti-parallel β-sheet to which each monomer contributes four β-strands. These β-sheets are situated at the center of the tetramer and positioned back to back. <scene name='82/829358/Interacab/1'>Ile107</scene> and <scene name='82/829358/Interacab/1'>Val122</scene> of monomer A are in direct van der Waals contact with the phenol ring of <scene name='82/829358/Interacab/1'>Phe87</scene> from monomer B.