Three-Dimensional Electron Microscopy at Molecular Resolution*

Emerging methods in cryo-electron microscopy allow determination of the three-dimensional architectures of objects ranging in size from small proteins to large eukaryotic cells, spanning a size range of more than 12 orders of magnitude. Advances in determining structures by “single particle” microscopy and by “electron tomography” provide exciting opportunities to describe the structures of subcellular assemblies that are either too large or too heterogeneous to be investigated by conventional crystallographic methods. Here, we review selected aspects of progress in structure determination by cryo-electron microscopy at molecular resolution, with a particular emphasis on topics at the interface of single particle and tomographic approaches. The rapid pace of development in this field suggests that comprehensive descriptions of the structures of whole cells and organelles in terms of the spatial arrangements of their molecular components may soon become routine.