Cryo‐electron microscopy coming of age: capsids to crystals

As a biophysical technique, electron microscopy has extraordinary scope from resolving tissues to atoms. Classical EM, including negative stain and metal shadowing, is invaluable for studying morphology, but cryo-EM has really broken the barriers to quantitative structure determination. Unlike X-ray crystallography or NMR, cryo-EM is often applied to larger and functional complexes where the importance of context can be appreciated, and in native or near-native conditions. Recent developments in detector technology have further advanced the reach of cryo-EM of particulate samples to atomic resolution, and a new wave of three-dimensional electron crystallography offers the promise of exploiting very small crystals in small number to also achieve atomic models. After an overview of the state of the field, specific examples of its application will include recent work on bacteriophage capsids, the structurally related herpesvirus capsids, and small picornaviruses where higher resolution is more readily achieved.