What is structural biology?
For the most part, biological research is an indirect science: it measures what happens as a result of a stimulus to an organism, a cell or a molecule. Often the stimulus is unknown and the consequence is recorded using a technical measurement readout; the result may be an enticing but rather disappointing portrayal of fundamental cellular processes.
Structural biology can help us to see some of the detail missing from this view and consequently is a powerful tool to unpick the intricate and exquisite choreography of life. For centuries, we have been able to visualise structures inside a cell, but even the most powerful microscopes are limited in the detail they provide, either by the sheer physical boundaries of magnification, or because the samples themselves are not alive and working. Structural biology methods delve beneath these limits bringing molecules to life in 3D and into sharper focus. It reaches to the very limits of how a molecule works and how its function can be modified.
The process of determining molecular structure can be long and frustrating – sometimes taking years. Mostly, proteins are the targets for structure analysis as these are the main ‘doing’ molecules of the cell. Proteins are built from a DNA template and the string of amino acids thus synthesized fold into very complex loops, sheets and coils – it might seem like a tangle, but this structure dictates how the protein will interact with other structures around it in order to undertake its duties in the cell. The elegant structures of molecules and the complexes they form can be breathtaking in their logic and symmetry, but they are also supreme in helping us to understand how cells actually work. Suddenly shapes, sizes and assemblies of molecules can be assigned to various compartments in cells and put into context with their surrounding environment. A key aim of structural cell biology is to build a landscape representation of cellular function. The emergent picture will be akin to a sophisticated and dynamic metropolis where molecular relationships are forged and broken, short- or long-lived and all are shaped by the inevitability of cell reproduction, aging and death.
To discover the 3D structure of a protein, the most common route is to crystallise it. This stabilises many identical protein molecules in a crystal lattice which, when bombarded with X-rays, provides diffraction data giving valuable information on the spatial relationships of atoms in the protein. From these data, the 3D structure can be built, from scratch if necessary, but more commonly in today’s structural biology laboratories, by comparison with other similar structures. The resulting image of a protein structure can depict its size, how it is folded up, what the overall ‘shape’ is and where any special ‘decorations’ are attached. These images are, of course, artificial; a protein doesn’t actually look like the images generated, the reality of protein structure in nature being dynamic and therefore more indistinct.
Some proteins are hard or impossible to crystallise in which case other techniques can be used to determine the structure. These other methods such as nuclear magnetic resonance, microscopy, electron tomography or mass spectroscopy give different views of proteins at different scales. So to get the richest and most accurate 3D structure of a protein, all of these techniques can be brought together to produce a protein structure that gives more information than just the space it fills. This is correlative structural biology – correlating information from many techniques into one structure that can tell you how the protein works, where it fits inside (or outside) the cell and which other molecules it interacts with. This view of a small part of the cell landscape can be used to identify proteins or even specific parts of proteins that can be targets of designer drugs; perhaps to disable a dysfunctional protein or to modify its behaviour. Structural biology can therefore bring unique information to drug or vaccine discovery programmes and be used thereafter to correlate efficacy with the specific changes at an atomic level. It is a key foundation for modern strategies to improve health for the future.
Integrated Structural Biology
It is no longer sufficient to determine simply the structure and biochemical properties of a protein in vitro. In line with the trend towards systems biology, a major challenge now is understanding how that protein functions dynamically within a larger macromolecular assembly or in a cellular pathway or even at the organism level.
Understanding dynamic processes that are co-ordinated at a cellular level is not possible using a single technology, but becomes potentially accessible through the integration of a number of approaches, spanning different resolution scales. Instruct offers scientists access to world-class structural biology infrastructures and expertise that make such integration possible more rapidly and will create a coherent forum for structural biology. This forum will stimulate closer collaboration between scientific communities and initiatives in structural, cell and systems biology. The infrastructure will be developed as a dynamic, distributed research infrastructure consisting of complementary major Centres across Europe providing peer-reviewed access to all of the core structural biology technologies for excellent scientific projects, developing the next generation of instrumentation in partnership with industry, and providing training for structural biologists in cutting edge techniques, and training for other disciplines that need to be able to utilise or interpret structural information in order to foster integrative cellular, systems and structural biology.
Instruct allows ongoing development of, and user access to, state-of-the-art sample preparation and characterisation facilities and core structure determination technologies (e.g. NMR, electron microscopy, and X-ray crystallography) as well as newer structural biology technologies that are developing at the interface with cell biology (cryo-EM tomography, correlative microscopy, X-ray imaging, single molecule techniques, in-cell NMR). Through the integration of structural data derived using different technologies and on different length and time scales in vitro and in cells, we will be able to understand, on the basis of detailed atomic structure, how proteins, protein complexes or whole pathogens interact dynamically with their functional environment. This will require substantial developments in computational biology and bioinformatics, but promises to allow us to see in atomic detail the mechanisms by which healthy cells function and diseases progress. This fundamental understanding will underpin our ability to provide new therapeutics to meet the grand challenges of an ageing society, public health and global pandemics.