2B15

The crystal structure of 2,4-dinitrophenol in complex with human transthyretin

Summary for 2B15

• Entry DOI: 10.2210/pdb2b15/pdb
• Related: 2B14 2B16
• Descriptor: Transthyretin, SULFATE ION, 2,4-DINITROPHENOL, ... (4 entities in total)
• Functional Keywords: amyloid, transthyretin, 2, 4-dinitrophenol, tetramer stabilizer, transport protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P02766
• Total number of polymer chains: 2
• Total formula weight: 28115.06

Authors

Morais-de-Sa, E.,Neto-Silva, R.M.,Pereira, P.J.,Saraiva, M.J.,Damas, A.M. (deposition date: 2005-09-15, release date: 2006-07-18, Last modification date: 2023-10-25)

Primary citation

Morais-de-Sa, E.,Neto-Silva, R.M.,Pereira, P.J.,Saraiva, M.J.,Damas, A.M.
The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin
ACTA CRYSTALLOGR.,SECT.D, 62:512-519, 2006

PubMed 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.

PubMed: 16627944
DOI: 10.1107/S0907444906006962

Experimental method

X-RAY DIFFRACTION (1.7 Å)