The rapid development of HIV protease inhibitor drugs between 1989 and 1995 is an early success story of structural biology. Structural biology is concerned with three-dimensional structures of biological molecules. The structure of a molecule crucial in the infectious cycle of HIV was first published in 1989. Only six years later the first drugs targeting this molecule appeared on the market, leading to a dramatic decrease in the death rate from AIDS. In the 15 years since, drug development in general has become increasingly dependent on structural biology. Knowledge of the molecular structure of pathogens often suggests ways to disrupt their function. Compared to the traditional trial-and-error approach this can eliminate years of development time and cut many millions of dollars in development costs. - The predominant method for obtaining molecular structures is X-ray crystallography, which accounts for 87% of all biological structures known today. Long-term large-scale investments by NIH into research facilities of industrial dimensions have increased the number of structures solved per year to nearly 10,000. Unfortunately, certain highly important molecules are difficult to solve with current X-ray techniques. These are the membrane proteins, which are the targets of more than 60% of the drugs on the market. There is an estimated 5,500-7,700 membrane proteins in the human body, but fewer than a dozen structures of these are currently known. This is mainly because membrane proteins are notoriously difficult to crystallize. Without crystals of sufficient size conventional X-ray crystallography is impossible. - Very recently, a new major X-ray technology has emerged that promises to expand the reach to membrane proteins. The construction of the world's first hard X-ray Free Electron Laser (XFEL) was completed in 2009. The first publication of exploratory XFEL work on a membrane protein appeared in February 2011. An XFEL instrument can work with crystals of much smaller sizes than are needed for conventional experiments, sizes attainable even with membrane proteins. However, extracting structural information from an XFEL experiment currently takes many months. In about 28% of all cases, XFEL data processing is faced with ambiguities that prevent the extraction of high-quality results, compromising biological interpretation. For XFEL experiments to realize their full potential, the data processing times need to be decreased by at least two orders of magnitude and the ambiguities need to be resolved. - We have extensive experience developing data processing software for conventional X-ray experiments, with open-source implementations in the Computational Crystallography Toolbox (CCTBX). Building on our internationally recognized expertise and the large set of modular tools in CCTBX, we will implement real-time processing of XFEL data. This will include resolving ambiguities in the data if present, so that high-quality structural information will be within reach for all types of pharmaceutically relevant molecules.
The development of new drugs is increasingly dependent on detailed knowledge of the molecular building blocks of life and disease carrying agents. X-ray crystallography has been the dominating technique for obtaining this knowledge. We are applying for resources that will allow us to extend the reach of X-ray crystallography and boost its efficiency. Investing in this work has the potential to save countless lives and hundreds of millions of dollars in drug development.
|Lyubimov, Artem Y; Uervirojnangkoorn, Monarin; Zeldin, Oliver B et al. (2016) Advances in X-ray free electron laser (XFEL) diffraction data processing applied to the crystal structure of the synaptotagmin-1 / SNARE complex. Elife 5:|
|Ginn, Helen Mary; Evans, Gwyndaf; Sauter, Nicholas K et al. (2016) On the release of cppxfel for processing X-ray free-electron laser images. J Appl Crystallogr 49:1065-1072|
|Waterman, David G; Winter, Graeme; Gildea, Richard J et al. (2016) Diffraction-geometry refinement in the DIALS framework. Acta Crystallogr D Struct Biol 72:558-75|
|Roessler, Christian G; Agarwal, Rakhi; Allaire, Marc et al. (2016) Acoustic Injectors for Drop-On-Demand Serial Femtosecond Crystallography. Structure 24:631-40|
|Young, Iris D; Ibrahim, Mohamed; Chatterjee, Ruchira et al. (2016) Structure of photosystem II and substrate binding at room temperature. Nature 540:453-457|
|Barnes, Christopher O; Kovaleva, Elena G; Fu, Xiaofeng et al. (2016) Assessment of microcrystal quality by transmission electron microscopy for efficient serial femtosecond crystallography. Arch Biochem Biophys 602:61-8|
|Alonso-Mori, R; Asa, K; Bergmann, U et al. (2016) Towards characterization of photo-excited electron transfer and catalysis in natural and artificial systems using XFELs. Faraday Discuss 194:621-638|
|Ginn, Helen Mary; Roedig, Philip; Kuo, Anling et al. (2016) TakeTwo: an indexing algorithm suited to still images with known crystal parameters. Acta Crystallogr D Struct Biol 72:956-65|
|Sierra, Raymond G; Gati, Cornelius; Laksmono, Hartawan et al. (2016) Concentric-flow electrokinetic injector enables serial crystallography of ribosome and photosystem II. Nat Methods 13:59-62|
|Lyubimov, Artem Y; Uervirojnangkoorn, Monarin; Zeldin, Oliver B et al. (2016) IOTA: integration optimization, triage and analysis tool for the processing of XFEL diffraction images. J Appl Crystallogr 49:1057-1064|
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