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Related Concept Videos

Regulation of Metabolism01:19

Regulation of Metabolism

Cellular needs and conditions vary from cell to cell and change within individual cells over time. For example, the required enzymes and energetic demands of stomach cells are different from those of fat storage cells, skin cells, blood cells, and nerve cells. Furthermore, a digestive cell works much harder to process and break down nutrients during the time that closely follows a meal compared with many hours after a meal. As these cellular demands and conditions vary, so do the amounts and...
Allosteric Regulation01:08

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
Epigenetic Regulation01:46

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Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.

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Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin)
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Allosteric modulation of DNA by small molecules.

David M Chenoweth1, Peter B Dervan

  • 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 12, 2009
PubMed
Summary

Small molecules called pyrrole-imidazole polyamides can disrupt cancer-driving gene expression by binding to DNA. This study reveals how these polyamides alter DNA structure, offering a new way to control gene networks chemically.

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Area of Science:

  • Molecular Biology
  • Chemical Biology
  • Structural Biology

Background:

  • Dysregulated gene expression, often due to transcription factor oversupply, drives human diseases, including cancer.
  • Targeting transcription factor-DNA interactions with small molecules offers a potential strategy for controlling aberrant gene expression.

Purpose of the Study:

  • To investigate the structural basis by which pyrrole-imidazole (Py/Im) polyamides disrupt transcription factor-DNA interfaces.
  • To provide a molecular understanding for the chemical control of gene networks.

Main Methods:

  • X-ray crystallography was used to determine the high-resolution structure of an 8-ring cyclic Py/Im polyamide bound to a specific DNA sequence.
  • Analysis of the crystal structure to understand the allosteric perturbations induced in the DNA helix.

Main Results:

  • The Py/Im polyamide binds to the DNA minor groove, inducing a 4 Å widening.
  • The binding event also causes major groove compression and a >18-degree bend in the DNA helix axis towards the major groove.
  • These structural changes represent an allosteric perturbation of the DNA helix.

Conclusions:

  • Pyrrole-imidazole polyamides can allosterically alter DNA helix structure.
  • This structural disruption provides a molecular mechanism for small molecules to interfere with transcription factor-DNA binding.
  • This finding supports the potential of small molecules for the chemical control of gene expression pathways in diseases.