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MicroED for the study of protein–ligand interactions and the potential for drug discovery

Abstract

Microcrystal electron diffraction (MicroED) is an electron cryo-microscopy (cryo-EM) technique used to determine molecular structures with crystals that are a millionth the size needed for traditional single-crystal X-ray crystallography. An exciting use of MicroED is in drug discovery and development, where it can be applied to the study of proteins and small molecule interactions, and for structure determination of natural products. The structures are then used for rational drug design and optimization. In this Perspective, we discuss the current applications of MicroED for structure determination of protein–ligand complexes and potential future applications in drug discovery.

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Fig. 1: Microcrystal electron diffraction structure of catalase with a bound haem and NADPH.
Fig. 2: I3C sites in proteinase K.
Fig. 3: Microcrystal electron diffraction facilitates the modelling of inhibitors within the protein structure.
Fig. 4: Membrane protein structures determined by MicroED.

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Acknowledgements

The Nannenga laboratory is supported by the National Institutes of Health R01GM124152 and R21GM135784 and the National Science Foundation DMR-1942084. The Gonen laboratory is supported by the National Institutes of Health P41GM136508 and by funds from the Howard Hughes Medical Institute.

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Correspondence to Brent L. Nannenga or Tamir Gonen.

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Nature Reviews Chemistry thanks Xiaodong Zou (who co-reviewed with Gerhard Hofer), Hongyi Xu and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Glossary

Lipidic cubic phase

(LCP). A lipid matrix that mimics a membrane and can stabilize and facilitate crystallization of membrane proteins.

Positive density

In a difference map, shows that there is signal in the data that is not being modelled and indicates where to add new atoms and molecules to the structural model.

Vitrification

The process of freezing water so quickly that it does not crystallize but becomes an amorphous solid.

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Clark, L.J., Bu, G., Nannenga, B.L. et al. MicroED for the study of protein–ligand interactions and the potential for drug discovery. Nat Rev Chem 5, 853–858 (2021). https://doi.org/10.1038/s41570-021-00332-y

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