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Annu Rev Biochem. 2015;84:499-517. doi: 10.1146/annurev-biochem-060614-034226. Epub 2015 Feb 26.

Cryogenic electron microscopy and single-particle analysis.

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Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; email:


About 20 years ago, the first three-dimensional (3D) reconstructions at subnanometer (<10-Å) resolution of an icosahedral virus assembly were obtained by cryogenic electron microscopy (cryo-EM) and single-particle analysis. Since then, thousands of structures have been determined to resolutions ranging from 30 Å to near atomic (<4 Å). Almost overnight, the recent development of direct electron detectors and the attendant improvement in analysis software have advanced the technology considerably. Near-atomic-resolution reconstructions can now be obtained, not only for megadalton macromolecular complexes or highly symmetrical assemblies but also for proteins of only a few hundred kilodaltons. We discuss the developments that led to this breakthrough in high-resolution structure determination by cryo-EM and point to challenges that lie ahead.


3D reconstruction; ab initio; electron microscopy; image processing; near-atomic resolution; projection matching

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