Assignment ( Hatters ) ( Transthyretin )

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B30001 Assignment (Hatters) - Transthyretin

Benjamin Andrikopoulos 759192

Introduction to TTR:

Transthyretin (TTR) is a protein in the blood (serum) and cerebrospinal fluid of humans that functions in the transport of the thyroid hormone thyroxine (T4) and retinol (also known as Vitamin A1). [1] It is secreted by the liver into the blood and by the choroid plexus into the cerebrospinal fluid. [2] Studies have shown that as less than 1% of TTR 's T4-binding sites (T4BS) in the blood are in use and occupied, new drug designs can be specialised and optimised to bind to these sites, thus preventing TTR misfolding, dissociation, and aggregation. [4] Amyloid diseases are associated with the misfolding and dissociation of the TTR tetramer and
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Figure 1. Three-dimensional cartoon style structure of transthyretin (TTR) showing two monomers/one dimer of the dimer-of-dimers quaternary structure (monomers pink and orange) at the binding interface. Stick style top view of AG10 (blue) highlighting two binding sites per tetramer and key binding serine and lysine residues S117 and K15 of TTR (green). All monomers of TTR contain 1 α-helix and an 8-stranded β-sheet with Greek-key topology.

Interaction differences - AG10 vs. tafamidis:

With AG10 binding to TTR, the dimethyl-pyrazole-like ring of AG10 sits deep within the T4BS cavity, forming two H-bonds to two Ser117 residues of subunits adjacent to each other. The –CH3 pair of the pyrazole ring are positioned into halogen binding pocket 3 (HBP 3), which is considered a hydrophobic area. [4] The terminal COOH group on the benzene ring allows for van der Waals interactions with the side chain amino groups of the two Lys15 residues directly on different monomers at the edge of the T4BS, with the F moiety in the para position fitting into HBP 1. These interactions close to the binding environment surrounding AG10 are protected in part from the surrounding solvent, leading to high affinity binding of AG10 to TTR. [4]

Contrasting with tafamidis hydrogen bonding is absent at the base of the binding pocket like with AG10, but the Cl substituents are instead located in HBP 3, where hydrophobically the subunits are bridged. [4] This absence of additional

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