The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin

Acta Crystallographica. Section D, Biological Crystallography
Eurico Morais-de-SáA M Damas

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 all...Continue Reading

Citations

Mar 10, 2009·Archives of Biochemistry and Biophysics·Raghu PullakhandamG Bhanuprakash Reddy
Nov 4, 2015·Acta Crystallographica. Section D, Biological Crystallography·Avik BanerjeeKanagaraj Sekar
Oct 24, 2013·Journal of Medicinal Chemistry·Ellen Y CotrinaGregorio Valencia
Feb 28, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Eszter Herczenik, Martijn F B G Gebbink

❮ Previous
Next ❯

Related Concepts

Related Feeds

Amyloidogenesis-associated Polyneuropathy

Amyloid deposits around nerves can damage and disrupt smooth information processing between the brain and organs. Here is the latest research on amyloidosis-associated polyneuropathies.

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.