Differentiating the solution structures and stability of transthyretin tetramer complexed with tolcapone and tafamidis using SEC-SWAXS and NMR.

ABSTRACT: Human transthyretin (TTR) is a homotetrameric protein involved in transporting thyroxine (T4) and retinol-binding protein within serum and cerebrospinal fluid. The disassociation of TTR's tetrameric structure can lead to the formation of biologically toxic TTR amyloid fibrils. Tolcapone, a small molecule currently under clinical trial, has shown potential as a TTR stabilizer and may act as an alternative to tafamidis, the conventional therapeutic agent used to prevent TTR dissociation. Using size-exclusion-chromatography-based small- and wide-angle X-ray scattering (SEC-SWAXS) complemented by nuclear magnetic resonance (NMR) spectroscopy, this study reveals the solution conformations of Apo-TTR and TTR complexed with tolcapone and tafamidis. Our results indicate that both compounds can bin

SUBMITTER: Shih O 

PROVIDER: S-EPMC12321038 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature