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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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Chemotaxis in Escherichia coli is a sensory-driven motility mechanism that enables bacteria to navigate chemical gradients, moving toward beneficial environments while avoiding harmful conditions. This process relies on a signal transduction system integrating external chemical cues with flagellar motor control.Chemoreceptors and Signal DetectionE. coli detects chemical gradients through methyl-accepting chemotaxis proteins (MCPs), which are membrane-bound chemoreceptors that sense attractants...
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Molecular chameleons adaptability in target binding.

Guanhong Bu1, Måns Eriksson1, Emma Rova Danelius1

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Summary
This summary is machine-generated.

Macrocycles, or molecular chameleons, can target previously undruggable proteins. Their conformational flexibility allows adaptation to various targets, aiding drug development for diseases like Hepatitis C, COVID-19, and cancer.

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Area of Science:

  • Medicinal Chemistry
  • Structural Biology
  • Drug Discovery

Background:

  • Up to 85% of human therapeutic proteomes are undruggable by traditional small molecules.
  • Macrocycles offer potential for modulating challenging biological targets.
  • These molecules exhibit conformational flexibility, acting as 'molecular chameleons'.

Purpose of the Study:

  • To explore the conformational adaptability of macrocycles in target binding.
  • To investigate three known macrocyclic drugs: paritaprevir, grazoprevir, and simeprevir.
  • To assess binding to drug transporters and COVID-19 related proteins.

Main Methods:

  • Molecular docking of experimental crystal, solution, and target-bound structures.
  • Analysis of conformational changes upon protein binding.
  • Comparison across multiple protein targets.

Main Results:

  • The macrocyclic core's conformational class dictates overall pharmacophore conformation.
  • This 'chameleonic group' influences conformational changes necessary for protein binding.
  • Identified specific binding patterns relevant to drug transporters and viral proteins.

Conclusions:

  • Macrocycle conformational adaptability is key to their broad target engagement.
  • Insights guide rational drug optimization for macrocyclic therapeutics.
  • Provides a basis for repurposing Hepatitis C inhibitors for COVID-19 and cancer therapies.