2B15: The Crystal Structure Of 2,4-Dinitrophenol In Complex With Human Transthyretin

Citation:
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.
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)
4
Transthyretin(Gene symbol: TTR)
Molecule annotation
Chemicals (6 molecules)
1
4
2
2
* Click molecule labels to explore molecular sequence information.

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