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Related Concept Videos

X-ray Diffraction of Biological Samples01:10

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X-ray diffraction or XRD is an analytical tool that utilizes X-rays to study ordered structures such as crystalline organic and inorganic samples, polycrystalline materials, proteins, carbohydrates, and drugs.
According to Bragg's law, when X-rays strike the sample positioned on a stage, the rays are  scattered by the electron clouds around the sample atoms. The  X-ray diffraction or scattering is caused by constructive interference of the X-ray waves that reflect off the internal...
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The size of the unit cell and the arrangement of atoms in a crystal may be determined from measurements of the diffraction of X-rays by the crystal, termed X-ray crystallography.
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Microcrystal Electron Diffraction of Small Molecules
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Visualizing drug binding interactions using microcrystal electron diffraction.

Max T B Clabbers1, S Zoë Fisher2,3, Mathieu Coinçon4,5

  • 1Department of Materials and Environmental Chemistry, Stockholm University, 106 91, Stockholm, Sweden.

Communications Biology
|August 2, 2020
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Summary
This summary is machine-generated.

Microcrystal electron diffraction (MicroED) now visualizes drug binding to proteins like human carbonic anhydrase II. This breakthrough enables detailed structural insights for drug discovery and fragment screening.

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Area of Science:

  • Structural biology
  • Biophysics
  • Drug discovery

Background:

  • Visualizing ligand binding is crucial for structure-based drug design and fragment screening.
  • Microcrystal electron diffraction (MicroED) offers potential for studying drug binding in small macromolecular crystals.
  • Previous studies have not unambiguously resolved drug binding interactions using electron diffraction alone.

Purpose of the Study:

  • To investigate the utility of MicroED for visualizing drug binding interactions.
  • To resolve the binding of a sulfonamide inhibitor to human carbonic anhydrase isoform II (HCA II).

Main Methods:

  • Utilizing MicroED on a conventional transmission electron microscope.
  • Collecting diffraction data from thin, hydrated microcrystals of HCA II soaked with acetazolamide (AZM).

Main Results:

  • High-quality MicroED data were efficiently collected from HCA II microcrystals.
  • The bound acetazolamide inhibitor was unequivocally fitted and resolved within the HCA II structure.
  • Demonstrated the capability of MicroED to resolve drug-protein interactions.

Conclusions:

  • MicroED is a viable method for visualizing drug binding interactions at high resolution.
  • MicroED can complement existing structural biology techniques like X-ray and neutron diffraction.
  • This technique holds promise for facilitating in-house fragment screening in drug discovery.