title: The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin.
abstract: Systemic deposition of transthyretin (TTR) amyloid fibrils is always observed in familial amyloidotic polyneuropathy, senile systemic amyloidosis and familial amyloidotic cardiomyopathy patients. Destabilization of the molecule leads to a cascade of events which result in fibril formation. The destabilization of a native protein with consequent conformational changes appears to be a common link in several human amyloid diseases. Intensive research has been directed towards finding small molecules that could work as therapeutic agents for the prevention/inhibition of amyloid diseases through stabilization of the native fold of the potentially amyloidogenic protein. This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures now determined allow a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.
authors.affiliation: Instituto de Biologia Molecular e Celular-IBMC, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
authors.forename: Eurico
authors.initials: E
authors.lastname: Morais-de-Sá
authors.forename: Ricardo Miguel
authors.initials: RM
authors.lastname: Neto-Silva
authors.forename: Pedro J B
authors.initials: PJ
authors.lastname: Pereira
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Saraiva
authors.forename: Ana M
authors.initials: AM
authors.lastname: Damas
mesh_terms: D019297:2,4-Dinitrophenol / Q000737:chemistry*; D019943:Amino Acid Substitution; D000686:Amyloidosis / Q000235:genetics*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010455:Peptides; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics
chemical_list: D010455:Peptides; D011228:Prealbumin; D019297:2,4-Dinitrophenol