The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin.
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.
Morais-de-Sá
Eurico
E
Instituto de Biologia Molecular e Celular-IBMC, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
Neto-Silva
Ricardo Miguel
RM
Pereira
Pedro J B
PJ
Saraiva
Maria J
MJ
Damas
Ana M
AM
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
D010455:Peptides; D011228:Prealbumin; D019297:2,4-Dinitrophenol