2B15: The Crystal Structure Of 2,4-Dinitrophenol In Complex With Human 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.
PDB ID: 2B15Download
MMDB ID: 40263
PDB Deposition Date: 2005/9/15
Updated in MMDB: 2007/11
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 2B15: tetrameric; determined by author and by software (PISA,PQS)
Molecular Components in 2B15
Label Count Molecule
Proteins (4 molecules)
Transthyretin(Gene symbol: TTR)
Molecule annotation
Chemicals (6 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB