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Abstract
The wild type protein, transthyretin (TTR), and over 120 genetic TTR variants are amyloidogenic and cause, respectively, sporadic and hereditary systemic TTR amyloidosis. The homotetrameric TTR contains two identical thyroxine binding pockets, occupation of which by specific ligands can inhibit TTR amyloidogenesis in vitro. Ligand binding stabilizes the tetramer, inhibiting its proteolytic cleavage and its dissociation. Here, we show with solution-state NMR that ligand binding induces long-distance conformational changes in the TTR that have not previously been detected by X-ray crystallography, consistently with the inhibition of the cleavage of the DE loop. The NMR findings, coupled with surface plasmon resonance measurements, have identified dynamic exchange processes underlying the negative cooperativity of binding of “monovalent” ligand tafamidis. In contrast, mds84, our prototypic “bivalent” ligand, which is a more potent stabilizer of TTR in vitro that occupies both thyroxine pockets and the intramolecular channel between them, has greater structural effects.
Highlights
The normal wild type plasma protein, transthyretin (TTR) is inherently amyloidogenic, forming pathogenic extracellular amyloid deposits, most notably in the heart and predominantly in elderly men
More than 25 very high-resolution X-ray structures have been reported of free wild type TTR as well as the complex of TTR bound to tafamidis and mds[84], respectively
The NMR backbone chemical shift assignment of wild type TTR has previously been reported under non-physiological pH and temperature conditions[16] and a new assignment at neutral pH has recently been deposited in the bmrb databank.[17]
Summary
The normal wild type plasma protein, transthyretin (TTR) is inherently amyloidogenic, forming pathogenic extracellular amyloid deposits, most notably in the heart and predominantly in elderly men. The first drug licensed for treatment of TTR amyloidosis, tafamidis,[4] was devised as a specific ligand for TTR and developed on the basis of its capacity to inhibit aggregation of TTR at low pH in vitro.[5] Other small molecules with this property have been extensively investigated[6] but all share the characteristic of being “monovalent”, that is, each ligand molecule only occupies a single thyroxine binding pocket in a single native tetrameric TTR molecule. We devised “bivalent” TTR ligand compounds that are avidly, pseudo-irreversibly, bound by native TTR under physiological conditions, occupying both binding pockets simultaneously and the intramolecular
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