THE BINDING OF D1ETHYLSTILBESTROL TO TRANSTHYRETIN - A CRYSTALLOGRAPHIC MODEL

摘要

Transthyretin (TTR) is a plasma protein which is known to form fibrillar extracellular deposits in patients suffering from three main types of pathologies, namely Senile Systemic Amyloidosis (SSA), Familial Amyloidotic Cardiomyopathy (FAC) and Famiiial Amyloidotic Polyneuropathy (FAP).Dissociation of the TTR tetramer is probably essential in the mechanism of amyloid formation and since the binding of small molecules to the TTR central channel stabilizes the tetramer, several compounds are being studied as a prospect for a non invasive therapeutic approach (1,2). Diethylstilbestrol {DES) is a synthetic estrogen that was shown to be a competitive inhibitor for thyroid hormone binding to TTR and therefore it may have a stabilizing effect over the protein quaternary structure (3). The crystallographic structure of TTR, first determined by C.Blake and collaborators, revealed a tetramer formed by four identical subunits, each of them consisting of two four stranded beta-sheets (4).In the present study, the three-dimensional structure of the TTR-DES complex was determined by X-ray crystallography with the aim of identifying the key features of DES that are responsible for its ability to bind TTR.