Sandbox Reserved 1105: Difference between revisions
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{{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | {{Sandbox_ESBS_2019}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
'''HUMAN TRANSTHYRETIN IN COMPLEX WITH DIBENZOFURAN-4,6-DICARBOXYLIC ACID''' | |||
== TTR functions == | |||
== TTR | |||
Human transthyretin (TTR) ([[1dvq]]) is a highly conserved homotetrameric transport protein. Identified in 1942, it was originally called prealbumin as it runs faster than albumin ([[1bm0]]) during SDS-PAGE <ref> Seibert FB, Nelson JW. Electrophoretic study of the blood protein response in tuberculosis. J Biol Chem 1942; 143: 29–38. </ref>. After discovering its binding and transport ability to thyroid hormones, it was given the name of “thyroxine-binding prealbumin” (TBPA). Finally, its actual name refers to an additional carrier function: '''trans'''ports '''thyr'''oxine (T4) and '''ret'''inol (vitamin A). | Human transthyretin (TTR) ([[1dvq]]) is a highly conserved homotetrameric transport protein. Identified in 1942, it was originally called prealbumin as it runs faster than albumin ([[1bm0]]) during SDS-PAGE <ref> Seibert FB, Nelson JW. Electrophoretic study of the blood protein response in tuberculosis. J Biol Chem 1942; 143: 29–38. </ref>. After discovering its binding and transport ability to thyroid hormones, it was given the name of “thyroxine-binding prealbumin” (TBPA). Finally, its actual name refers to an additional carrier function: '''trans'''ports '''thyr'''oxine (T4) and '''ret'''inol (vitamin A). | ||
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== Human TTR | == Human TTR == | ||
=== | === 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 depressions, termed halogen binding pockets (HBPs). They have a two-fold symmetry and confer a hydrophobic surface to the protein. 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 are involved in the binding of the natural ligand, the thyroxine (T4). | 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 depressions, termed halogen binding pockets (HBPs). They have a two-fold symmetry and confer a hydrophobic surface to the protein. 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 are involved in the binding of the natural ligand, the thyroxine (T4). | ||
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=== TTR | === TTR with natural ligands === | ||
The TTR – ligand interaction provides kinetic stabilization the protein. The more the affinity is high, the more the ligand stabilizes the complex. The dissociation constants with T4 and retinol-binding protein (RBP) are respectively from 1,1.10-7 to 1,5.10-7 M <ref name = "Monaco"> Monaco, H., Rizzi, M., & Coda, A. (1995). Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science, 268(5213), 1039–1041. doi:10.1126/science.7754382</ref>. | The TTR – ligand interaction provides kinetic stabilization the protein. The more the affinity is high, the more the ligand stabilizes the complex. The dissociation constants with T4 and retinol-binding protein (RBP) are respectively from 1,1.10-7 to 1,5.10-7 M <ref name = "Monaco"> Monaco, H., Rizzi, M., & Coda, A. (1995). Structure of a complex of two plasma proteins: transthyretin and retinol-binding protein. Science, 268(5213), 1039–1041. doi:10.1126/science.7754382</ref>. | ||
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== Disease == | == Disease == | ||
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. doi: 10.1039/c4cp04549a. 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> | |||
Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="Klabunde" /> | Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="Klabunde" /> | ||
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==Drug development== | ==Drug development== | ||
=== | === Non-steroidal anti-inflammatory drugs=== | ||
[[Image: Drugstructure.png | thumb | left | alt=Puzzle globe| Structures of thyroxine (T4), the natural ligand of TTR and other designed TTR fibril formation inhibitors| 200 px]] | [[Image: Drugstructure.png | thumb | left | alt=Puzzle globe| Structures of thyroxine (T4), the natural ligand of TTR and other designed TTR fibril formation inhibitors| 200 px]] | ||
