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

doi:10.1107/S0907444906006962

Paper

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

Published May 1, 2006 · Eurico Morais-de-Sá, R. M. Neto-Silva, P. Pereira

Acta crystallographica. Section D, Biological crystallography

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15

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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.

Study Snapshot

2,4-dinitrophenol shows potential as a therapeutic agent for amyloid diseases by stabilizing native folds of potentially amyloidogenic proteins, potentially preventing or inhibiting amyloid diseases.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

Neuritogenesis and neuronal differentiation promoted by 2,4‐dinitrophenol, a novel anti‐amyloidogenic compound

2,4-dinitrophenol promotes neuritogenesis and neuronal differentiation, suggesting it may be a useful lead compound for developing novel therapeutic approaches targeting neurite dystrophy and synaptic dysfunction in neurodegenerative pathologies like Alzheimer's disease.

Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor.

Iododiflunisal effectively inhibits amyloid fibril formation by increasing the stability of human transthyretin, offering potential for more specific and effective drugs for familial amyloidotic polyneuropathy patients.

The Crystal Structure of Transthyretin in Complex with Diethylstilbestrol

Diethylstilbestrol (DES) stabilizes transthyretin's tetramer, potentially acting as an amyloid inhibitor and aiding in the design of more powerful drugs against TTR amyloidosis.

Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative.

Novel diflunisal derivatives show high selectivity and efficiency as TTR stabilizers and inhibitors of fibril formation in familial amyloidotic polyneuropathy patients.

The β-strand D of transthyretin trapped in two discrete conformations

The engineered transthyretin variant Ala108Tyr/Leu110Glu is less amyloidogenic than wild-type TTR, with crystal structures showing similar packing arrangements in both P2 and C2 crystal forms.

Citations

Inhibitors of Transthyretin Amyloidosis: How to Rank Drug Candidates Using X-ray Crystallography Data

X-ray crystallography data can help rank potential TTR amyloidosis inhibitors based on their ability to compaction the protein's quaternary structure.

Label-free drug interaction screening via Raman microscopy

The thermostable Raman interaction profiling (TRIP) technique allows for low-concentration and low-dose screening of protein-ligand binding in physiologically relevant conditions, offering a valuable tool for drug development.

The Transthyretin/Oleuropein Aglycone Complex: A New Tool against TTR Amyloidosis

Oleuropein (OleA) stabilizes transthyretin (TTR) and prevents its dissociation into monomers, potentially offering a new treatment for degenerative diseases associated with TTR misfolding.

Physiological Metals Can Induce Conformational Changes in Transthyretin Structure: Neuroprotection or Misfolding Induction?

Physiological metals can induce conformational changes in transthyretin, potentially guiding its A-scavenging role or accelerating its amyloidogenic process.

The putative role of some conserved water molecules in the structure and function of human transthyretin.

Conserved water molecules in human transthyretin play crucial roles in stabilizing its dimeric structure, maintaining its geometry, and controlling its orientation and dynamics.