Visualizing drug binding interactions using microcrystal electron diffraction
| Autor: | Xiaodong Zou, S. Zoë Fisher, Max T. B. Clabbers, Hongyi Xu, Mathieu Coincon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Neutron diffraction Drug Evaluation Preclinical Medicine (miscellaneous) Electrons 010402 general chemistry Crystallography X-Ray Ligands 01 natural sciences Carbonic Anhydrase II General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Microscopy Electron Transmission Cryoelectron microscopy Screening method Humans lcsh:QH301-705.5 media_common Conventional transmission electron microscope Drug discovery Chemistry 0104 chemical sciences Acetazolamide Crystallography 030104 developmental biology Structural biology Electron diffraction lcsh:Biology (General) Drug screening Pharmaceutical Preparations General Agricultural and Biological Sciences Macromolecule |
| Zdroj: | Communications Biology Communications Biology, Vol 3, Iss 1, Pp 1-8 (2020) |
| ISSN: | 2399-3642 |
| Popis: | Visualizing ligand binding interactions is important for structure-based drug design and fragment-based screening methods. Rapid and uniform soaking with potentially reduced lattice defects make small macromolecular crystals attractive targets for studying drug binding using microcrystal electron diffraction (MicroED). However, so far no drug binding interactions could unambiguously be resolved by electron diffraction alone. Here, we use MicroED to study the binding of a sulfonamide inhibitor to human carbonic anhydrase isoform II (HCA II). We show that MicroED data can efficiently be collected on a conventional transmission electron microscope from thin hydrated microcrystals soaked with the clinical drug acetazolamide (AZM). The data are of high enough quality to unequivocally fit and resolve the bound inhibitor. We anticipate MicroED can play an important role in facilitating in-house fragment screening for drug discovery, complementing existing methods in structural biology such as X-ray and neutron diffraction. Clabbers et al. utilize MicroED to present the structure of both apo and inhibitor-bound human carbonic anhydrase II at a high resolution to clearly identify the interaction of the inhibitor, acetazolamide. This method eases the difficulty of both crystallizing the protein and soaking the inhibitor in a smaller protein crystal. |
| Databáze: | OpenAIRE |
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