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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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.
The authors declare no competing interests.
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- 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.
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