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Related Concept Videos

Intrinsically Disordered Proteins02:18

Intrinsically Disordered Proteins

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Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
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Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
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Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA
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Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA

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Targeting disordered proteins with small molecules using entropy.

Gabriella T Heller1, Pietro Sormanni1, Michele Vendruscolo1

  • 1Department of Chemistry, University of Cambridge, Cambridge, UK.

Trends in Biochemical Sciences
|August 16, 2015
PubMed
Summary
This summary is machine-generated.

Small molecules can target disordered proteins, which are linked to diseases, by altering their conformational space. This binding mechanism expands the protein

Keywords:
bindingdisordered proteinsentropic expansionentropysmall molecule

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Area of Science:

  • Biochemistry
  • Drug Discovery
  • Structural Biology

Background:

  • The human proteome contains numerous intrinsically disordered proteins (IDPs).
  • IDPs are associated with various human diseases, yet lack clinically approved drugs targeting their monomeric forms.
  • Understanding small molecule binding mechanisms to these proteins is limited.

Purpose of the Study:

  • To explore mechanisms by which small molecules can bind to and modulate disordered proteins.
  • To address the challenge of targeting IDPs for therapeutic intervention.

Main Methods:

  • General thermodynamic principles of intermolecular binding (enthalpic and entropic contributions).
  • Specific analysis of small molecule binding to disordered proteins.
  • Focus on conformational space modulation.

Main Results:

  • Small molecules can bind to disordered proteins by influencing their conformational ensemble.
  • A key binding mechanism involves creating an 'entropic expansion', populating more protein conformations.
  • This modulation of conformational space offers a pathway for therapeutic targeting.

Conclusions:

  • Small molecules can effectively target intrinsically disordered proteins.
  • Modulating the conformational space of IDPs via entropic expansion is a viable therapeutic strategy.
  • Further research into these binding mechanisms can facilitate drug development for IDP-related diseases.