Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic 
properties that has been linked to the development of familial amyloidotic 
polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic 
amyloidosis. The in vivo role of TTR is associated with transport of thyroxine 
hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR 
is a rate-limiting step in the process of TTR amyloid formation, and ligands 
with the ability to bind within the thyroxin binding site (TBS) can stabilize 
the tetramer, a feature that is currently used as a therapeutic approach for 
FAP. Several different flavonoids have recently been identified that impair 
amyloid formation. The flavonoid luteolin shows therapeutic potential with low 
incidence of unwanted side effects. In this work, we show that luteolin 
effectively attenuates the cytotoxic response to TTR in cultured neuronal cells 
and rescues the phenotype of a Drosophila melanogaster model of FAP. The 
plant-derived luteolin analogue cynaroside has a glucoside group in position 7 
of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR 
tetramers and thus prevents a cytotoxic effect. We generated high-resolution 
crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in 
complex with luteolin. The results show that the A-ring of luteolin, in contrast 
to what was previously suggested, is buried within the TBS, consequently 
explaining the lack of activity from cynaroside. The flavonoids represent an 
interesting group of drug candidates for TTR amyloidosis. The present 
investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We 
also show an alternative orientation of luteolin within the TBS which could 
represent a general mode of binding of flavonoids to TTR and is of importance 
concerning the future design of tetramer stabilizing drugs.