Sandbox Reserved 1105: Difference between revisions

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.  

And <scene name='82/829358/Aabis/1'>Phe64</scene> is in van der Waals contact with <scene name='82/829358/Aabis/1'>Cys10</scene> via <scene name='82/829358/Aabis/1'>Pro11</scene> in monomer A. Each monomer contain a single cysteine (<scene name='82/829358/Cys/1'>Cys10</scene>), 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>.

TTR is a specific carrier of RBP ([[1ggl]]). RBPs have a molecular mass of 21 kDa. They are composed of an eight-stranded β-barrel and a C-terminal α-helix.  

One tetramer of TTR can bind two molecules of RBP in vitro (1:2 stoichiometry). However, when we isolate the TTR-RBP complex from the plasma (in vivo) we find a 1:1 stoichiometry <ref name= "Naylor"> "Naylor, H. M., & Newcomer, M. E. (1999). The Structure of Human Retinol-Binding Protein (RBP) with Its Carrier Protein Transthyretin Reveals an Interaction with the Carboxy Terminus of RBP†,‡. Biochemistry, 38(9), 2647–2653. doi:http://dx.doi.org/10.1021/bi982291i"</ref> .  

The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. PMID:25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> P.Gambetti, C. Russo. Human brain amyloidoses. Neuphrol Dial Transplant. 1998; 13 [Suppl 7] : 33-40</ref>

<Structure load='1dvu' size='340' frame='true' align='right' caption='Crystal Structure of human transthyretin in complex with dibenzofuran-4,6-dicarboxylic acid from homo sapiens gene in Escherichia coli, resolution 2.05Å (PDB entry : [[1dvu]]) ' scene='Insert optional scene name here' />

4,6-dicarboxylate derivative of dibenzofuran (DDBF) is bounded according two symmetric equivalent modes <ref name="Petrassi">PMID:15869287</ref>. Indeed, DDBF wears a tricyclic ring system, with 2 hydrogen bond donors and 5 hydrogen bond acceptors, allowing to bound the dimer-dimer interface of the TTR cavity <ref name="National Center for Biotechnology Information">[https://pubchem.ncbi.nlm.nih.gov/compound/Dibenzofuran-4_6-dicarboxylic-acid Link text], PubChem Database. CID:3022(accessed on Dec. 26, 2019).</ref><ref name="Klabunde">PMID:10742177</ref>. Thanks to the complementarity of shape and hydrophobicity, DDBF enters nicely the outer portion of HBPs pockets <ref name="Petrassi "/>. Besides, the tricyclic ring system interacts with <scene name='83/832920/Lys15_leu17_and_ala108/1'>Lys15, Leu17 and Ala108</scene> from two adjacent TTR subunits <ref name="Petrassi"/>.  Additionally, carboxylates at the position 4 and 6 of DDBF make electrostatic interactions at the entrance of HBP1 and HBP1' with <scene name='83/832920/Lys15/3'>Lys15</scene> on the ε-NH3+ groups <ref name="Petrassi"/>.  

TTR in complex with dibenzofuran-4,6-dicarboxylic acid keeps the general apo-structure, with water molecules bind to HBP3 and HBP3’ cavities of TTR <ref name="Klabunde">PMID:10742177</ref>. There is not conformational change of <scene name='83/832920/Ser117/1'>Ser117</scene> and <scene name='83/832920/Thr119/1'>Thr119</scene> of TTR, contrary to other inhibitor, unlike most NSAID.  

Consequently, DDBF creates a bridge between two adjacent subunits stabilized by ionic and hydrophobic interactions.  

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