Perspectives in the field of Structural Biology

No-one could have foreseen that Julian Schwinger's calculations on the energy changes encountered by an electron moving on a circular path could result in construction of tools that have had a major impact on biological sciences and the discovery of new pharmaceuticals. Over the past forty years Synchrotron radiation has been successfully applied to a wealth of fundamental problems in life sciences, yielding dramatic improvements in the understanding of biological and chemical phenomena. A closely related area of new developments is Electron Diffraction, offering direct ways for atomic resolution structure determinations on crystals many million times smaller than those used in routine X-ray studies. Structural biologists are at last living the dream of visualizing macromolecules to uncover their function: scale up from the atomic to the cellular level. But... it means integrating different technologies, and that is no easy feat! From more than a century the field's premiere method has been X-ray crystallography. But some biomolecules are simply too big or small to crystallize. And some biomolecules change shape or orientation as they work, which is not captured by static crystallization. Some of the approaches, such as Cryogenic Electron Microscopy (cryo-EM) or chemist's stalwart Nuclear Magnetic Resonance (NMR) imaging, reveal molecular shapes, size and orientation at near-atom-level resolution without the need to make crystals. But not every method works for every protein, nucleic acid, polysaccharide or other biomolecule inside a living cell. No single method is likely to be sufficient to probe the dynamic behavior or intricate interactions taking place in a cell. The most powerful insights will come from hybrid methodologies that integrate the images from several different tools. The combination is very much larger than the sum of the parts. Such hybrid, or integrative, approaches will help researches to probe deep basic-science questions, but also reveal details that are useful to drug developers. Large proteins found in the cell membranes are often targets for therapeutic drugs, and high resolution hybrid methods have the potential to show in atomic detail how a drug interacts with a receptor.