Integrating cryo-EM and NMR data

Single-particle cryo-electron microscopy (cryo-EM) is increasingly used as a technique to determine the atomic structure of challenging biological systems. Recent advances in microscope engineering, electron detection, and image processing have allowed the structural determination of bigger and more flexible targets than possible with the complementary techniques X-ray crystallography and NMR spectroscopy. However, there exist many biological targets for which atomic resolution cannot be currently achieved with cryo-EM, making unambiguous determination of the protein structure impossible. Although determining the structure of large biological systems using solely NMR is often difficult, highly complementary experimental atomic-level data for each molecule can be derived from the spectra, and used in combination with cryo-EM data. We review here strategies with which both techniques can be synergistically combined, in order to reach detail and understanding unattainable by each technique acting alone; and the types of biological systems for which such an approach would be desirable.